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Cited by 345Hemoglobin structure and functionBacterial Genetics and BiotechnologyEscherichia coli research studies

Heme Synthesis and Acquisition in Bacterial Pathogens

Open access
Choby, Jacob E., Skaar, Eric P.·2016·Journal of Molecular Biology
DOI 10.1016/j.jmb.2016.03.018PMC PMC5125930
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Abstract

Bacterial pathogens require the iron-containing cofactor heme to cause disease. Heme is essential to the function of hemoproteins, which are involved in energy generation by the electron transport chain, detoxification of host immune effectors, and other processes. During infection, bacterial pathogens must synthesize heme or acquire heme from the host; however, host heme is sequestered in high-affinity hemoproteins. Pathogens have evolved elaborate strategies to acquire heme from host sources, particularly hemoglobin, and both heme acquisition and synthesis are important for pathogenesis. Paradoxically, excess heme is toxic to bacteria and pathogens must rely on heme detoxification strategies. Heme is a key nutrient in the struggle for survival between host and pathogen, and its study has offered significant insight into the molecular mechanisms of bacterial pathogenesis.

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Crossref · 10.1016/j.jmb.2016.03.018

Cites

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Claims the paper makes

0 of 520 cited sources checked · 0 supported · 0 flagged

  • Premisecitation

    Pathogens have evolved strategies to acquire heme from host sources, especially hemoglobin.

    “Pathogens have evolved elaborate strategies to acquire heme from host sources, particularly hemoglobin”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [102] Mazmanian SK Skaar EP Gaspar AH Humayun M Gornicki P Jelenska J Passage of heme-iron across the envelope of Staphylococcus aureus Science 299 2003 906 909 12574635 source

      Not checked in the free run.

  • Premisereasoning

    During infection, bacterial pathogens must either synthesize heme or acquire it from the host.

    “During infection, bacterial pathogens must synthesize heme or acquire heme from the host; however, host heme is sequestered in high-affinity hemoproteins.”
    Quote in the paperSubstantial claim
  • Interpretationreasoning

    Pathogens must rely on heme detoxification strategies.

    “pathogens must rely on heme detoxification strategies”
    Quote in the paperSubstantial claim
  • Premisenone given

    Heme is essential for hemoprotein functions including energy generation and detoxification of host immune effectors.

    “Heme is essential to the function of hemoproteins, which are involved in energy generation by the electron transport chain, detoxification of host immune effectors, and other processes.”
    Quote in the paperSubstantial claim
  • Premisecitation

    Cells rely on heme for the function of catalase, nitric oxide synthase, hemoglobin, and other conserved enzymes.

    “cells rely on heme for the function of many widely conserved enzymes including catalase, nitric oxide synthase, hemoglobin (Hb), and others”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [1] Chen JJ London IM Hemin enhances the differentiation of mouse 3T3 cells to adipocytes Cell 26 1981 117 122 6799206 source

      Not checked in the free run.

    • cites [2] Shelver D Kerby RL He Y Roberts GP CooA, a CO-sensing transcription factor from Rhodospirillum rubrum, is a CO-binding heme protein Proc Natl Acad Sci USA 94 1997 11216 11220 9326589 PMC23420 source

      Not checked in the free run.

    • cites [3] Faller M Matsunaga M Yin S Loo JA Guo F Heme is involved in microRNA processing Nat Struct Mol Biol 14 2007 23 29 17159994 source

      Not checked in the free run.

    • cites [4] Bonyhady RE Hendry IA Hill CE McLennan IS Effects of haemin on neurones derived from the neural crest Dev Neurosci 5 1982 125 129 6127199 source

      Not checked in the free run.

  • Classified as probably not a substantial claim. 33
  • May combine two claims. 114
  • The quote only partly states this claim. 1

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    Heme is a porphyrin ring complexed with iron and serves as a redox-active moiety required for many cellular proteins.

    “Heme, a porphyrin ring complexed with iron, serves as a redox active moiety required for the function of many cellular proteins.”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [1] Chen JJ London IM Hemin enhances the differentiation of mouse 3T3 cells to adipocytes Cell 26 1981 117 122 6799206 source

      Not checked in the free run.

    • cites [2] Shelver D Kerby RL He Y Roberts GP CooA, a CO-sensing transcription factor from Rhodospirillum rubrum, is a CO-binding heme protein Proc Natl Acad Sci USA 94 1997 11216 11220 9326589 PMC23420 source

      Not checked in the free run.

    • cites [3] Faller M Matsunaga M Yin S Loo JA Guo F Heme is involved in microRNA processing Nat Struct Mol Biol 14 2007 23 29 17159994 source

      Not checked in the free run.

    • cites [4] Bonyhady RE Hendry IA Hill CE McLennan IS Effects of haemin on neurones derived from the neural crest Dev Neurosci 5 1982 125 129 6127199 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Iron acts alone or in iron-sulfur clusters as a prosthetic moiety for oxidoreductase, nitrogenase, hydrogenase, dehydrogenase, and hydratase enzyme families.

    “iron can act alone or in iron–sulfur clusters as a prosthetic moiety for members of the oxidoreductase, nitrogenase, hydrogenase, dehydrogenase, and hydratase enzyme families [7–12].”
    Quote in the paperNot a substantial claim0 of 6 sources checked
    • cites [7] Kessler D Leibrecht I Knappe J Pyruvate-formate-lyasedeactivase and acetyl-CoA reductase activities of Escherichia coli reside on a polymeric protein particle encoded by adhE FEBS Lett 281 1991 59 63 2015910 source

      Not checked in the free run.

    • cites [8] Yamamoto I Saiki T Liu SM Ljungdahl LG Purification and properties of NADP-dependent formate dehydrogenase from Clostridium thermoaceticum, a tungsten–selenium–iron protein J Biol Chem 258 1983 1826 1832 6822536 source

      Not checked in the free run.

    • cites [9] Peters JW Lanzilotta WN Lemon BJ Seefeldt LC X-ray crystal structure of the Fe-only hydrogenase (CpI) from Clostridium pasteurianum to 1.8 Angstrom resolution Science 282 1998 1853 1858 9836629 source

      Not checked in the free run.

    • cites [10] Nagashima S Nakasako M Dohmae N Tsujimura M Takio K Odaka M Novel non-heme iron center of nitrile hydratase with a claw setting of oxygen atoms Nat Struct Biol 5 1998 347 351 9586994 source

      Not checked in the free run.

    • cites [11] Johnson DC Dean DR Smith AD Johnson MK Structure, function, and formation of biological iron–sulfur clusters Annu Rev Biochem 74 2005 247 281 15952888 source

      Not checked in the free run.

    • cites [12] Shomura Y Yoon KS Nishihara H Higuchi Y Structural basis for a [4Fe–3S] cluster in the oxygen-tolerant membrane-bound [NiFe]-hydrogenase Nature 479 2011 253 256 22002607 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Both heme acquisition and heme synthesis are important for bacterial pathogenesis.

    “both heme acquisition and synthesis are important for pathogenesis”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Heme functions as an electron shuttle in electron transport chain enzymes and is required for cellular respiration.

    “Heme functions as an electron shuttle in enzymes of the electron transport chain and is required for cellular respiration.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [22] Rieske JS Composition, structure and function of complex III of the respiratory chain Biochim Biophys Acta 456 1976 195 247 788795 source

      Not checked in the free run.

    • cites [23] Omura T Sato R The carbon monoxide-binding pigment of liver microsomes. I. Evidence for its hemoprotein nature J Biol Chem 239 1964 2370 2378 14209971 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    Nearly all organisms must satisfy their heme requirement through synthesis or acquisition.

    “Thus, nearly all organisms must satisfy the requirement for heme through either synthesis or acquisition.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Heme is involved in signaling, gas sensing, microRNA processing, and cellular differentiation.

    “Heme is also an important molecule involved in diverse cellular processes including signaling, gas sensing, microRNA processing, and cellular differentiation [1–4].”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [1] Chen JJ London IM Hemin enhances the differentiation of mouse 3T3 cells to adipocytes Cell 26 1981 117 122 6799206 source

      Not checked in the free run.

    • cites [2] Shelver D Kerby RL He Y Roberts GP CooA, a CO-sensing transcription factor from Rhodospirillum rubrum, is a CO-binding heme protein Proc Natl Acad Sci USA 94 1997 11216 11220 9326589 PMC23420 source

      Not checked in the free run.

    • cites [3] Faller M Matsunaga M Yin S Loo JA Guo F Heme is involved in microRNA processing Nat Struct Mol Biol 14 2007 23 29 17159994 source

      Not checked in the free run.

    • cites [4] Bonyhady RE Hendry IA Hill CE McLennan IS Effects of haemin on neurones derived from the neural crest Dev Neurosci 5 1982 125 129 6127199 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Heme is important for cellular processes of most organisms and essential to many lifeforms.

    “The tetrapyrrole cofactor heme is important for the cellular processes of most organisms and essential to many lifeforms across domains of life.”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [1] Chen JJ London IM Hemin enhances the differentiation of mouse 3T3 cells to adipocytes Cell 26 1981 117 122 6799206 source

      Not checked in the free run.

    • cites [2] Shelver D Kerby RL He Y Roberts GP CooA, a CO-sensing transcription factor from Rhodospirillum rubrum, is a CO-binding heme protein Proc Natl Acad Sci USA 94 1997 11216 11220 9326589 PMC23420 source

      Not checked in the free run.

    • cites [3] Faller M Matsunaga M Yin S Loo JA Guo F Heme is involved in microRNA processing Nat Struct Mol Biol 14 2007 23 29 17159994 source

      Not checked in the free run.

    • cites [4] Bonyhady RE Hendry IA Hill CE McLennan IS Effects of haemin on neurones derived from the neural crest Dev Neurosci 5 1982 125 129 6127199 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Iron is nearly universally required for life, with only a few exceptions.

    “Like heme, iron is nearly universally required for life, and only a few exceptions have been identified [5,6].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [5] Posey JE Gherardini FC Lack of a role for iron in the Lyme disease pathogen Science 288 2000 1651 1654 10834845 source

      Not checked in the free run.

    • cites [6] Archibald F Lactobacillus plantarum, an organism not requiring iron FEMS Microbiol Lett 19 1983 29 32 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Iron-binding proteins transport iron, protect host cells from iron-mediated oxidative damage, and keep iron from pathogens.

    “Iron-binding proteins function to transport iron, protect host cells from iron-mediated oxidative damage, and keep iron from pathogens.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [15] Cassat JE Skaar EP Iron in infection and immunity Cell Host Microbe 13 2013 509 519 23684303 PMC3676888 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Bacterial pathogens have developed tactics to overcome iron limitation and elaborate high-affinity iron receptors and chelators.

    “bacterial pathogens have developed exquisite tactics to overcome iron limitation and elaborate high-affinity iron receptors and chelators”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [15] Cassat JE Skaar EP Iron in infection and immunity Cell Host Microbe 13 2013 509 519 23684303 PMC3676888 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In serum, heme is immediately bound by albumin (kd ≈ 10 nM) and then transferred to hemopexin (kd < 1 pM).

    “In serum, heme is immediately bound by the highly abundant albumin (kd ≈ 10 nM) then transferred to hemopexin (kd < 1 pM) [30].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [30] Tolosano E Altruda F Hemopexin: structure, function, and regulation DNA Cell Biol 21 2002 297 306 12042069 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Humans and other metazoa synthesize heme through steps in mitochondria and cytosol; the Shemin pathway begins with condensation of glycine and succinyl-CoA to form ALA.

    “Humans and other metazoa synthesize heme through a variety of steps in the mitochondria and cytosol. This pathway, called the Shemin or four-carbon pathway, begins with the condensation of glycine and succinyl-CoA to form the committed precursor δ-aminolevulinic acid (ALA) [19–21].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [19] Wriston JC Jr Lack L Shemin D The mechanism of porphyrin formation; further evidence on the relationship of the citric acid cycle and porphyrin formation J Biol Chem 215 1955 603 611 13242557 source

      Not checked in the free run.

    • cites [20] Kikuchi G Shemin D Bachmann BJ The enzymic synthesis of delta-aminolevulinic acid Biochim Biophys Acta 28 1958 219 220 13535711 source

      Not checked in the free run.

    • cites [21] Hamza I Dailey HA One ring to rule them all: trafficking of heme and heme synthesis intermediates in the metazoans Biochim Biophys Acta 2012 1823 1617 1632 PMC3412874 22575458

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Heme is delivered to cells expressing the hemopexin receptor, and these cells degrade heme using heme oxygenases.

    “The heme is delivered to cells expressing the hemopexin receptor; these cells then degrade the heme using heme oxygenases [30].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [30] Tolosano E Altruda F Hemopexin: structure, function, and regulation DNA Cell Biol 21 2002 297 306 12042069 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    A series of enzymes produces protoporphyrin IX from ALA, and iron is inserted to form protoheme IX.

    “A series of enzymes produces protoporphyrin IX from ALA and iron is inserted, forming protoheme IX.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [19] Wriston JC Jr Lack L Shemin D The mechanism of porphyrin formation; further evidence on the relationship of the citric acid cycle and porphyrin formation J Biol Chem 215 1955 603 611 13242557 source

      Not checked in the free run.

    • cites [20] Kikuchi G Shemin D Bachmann BJ The enzymic synthesis of delta-aminolevulinic acid Biochim Biophys Acta 28 1958 219 220 13535711 source

      Not checked in the free run.

    • cites [21] Hamza I Dailey HA One ring to rule them all: trafficking of heme and heme synthesis intermediates in the metazoans Biochim Biophys Acta 2012 1823 1617 1632 PMC3412874 22575458

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Hemoglobin contains about two-thirds of the body's iron, and a single erythrocyte contains more than 280 million molecules of Hb.

    “Hb contains about two-thirds of the body's iron, and a single erythrocyte contains more than 280 million molecules of Hb [15,24].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [15] Cassat JE Skaar EP Iron in infection and immunity Cell Host Microbe 13 2013 509 519 23684303 PMC3676888 source

      Not checked in the free run.

    • cites [24] Bridges KR Seligman PA Disorders of Iron Metabolism J.B Lippincott Company New York 1995

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Nutritional immunity includes host manipulation of manganese, zinc, and other transition metals to starve or intoxicate pathogens.

    “Nutritional immunity has since been expanded to include the host processes that manipulate local levels of manganese, zinc, and other transition metals in order to metal starve or intoxicate the invading pathogens”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [15] Cassat JE Skaar EP Iron in infection and immunity Cell Host Microbe 13 2013 509 519 23684303 PMC3676888 source

      Not checked in the free run.

    • cites [16] Hood MI Skaar EP Nutritional immunity: transition metals at the pathogen-host interface Nat Rev Microbiol 10 2012 525 537 22796883 PMC3875331 source

      Not checked in the free run.

    • cites [17] Zackular JP Chazin WJ Skaar EP Nutritional immunity: S100 proteins at the host–pathogen interface J Biol Chem 290 2015 18991 18998 26055713 PMC4521021 source

      Not checked in the free run.

    • cites [18] Juttukonda LJ Skaar EP Manganese homeostasis and utilization in pathogenic bacteria Mol Microbiol 97 2015 216 228 25898914 PMC4631260 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Hemoproteins involved in tissue oxygen homeostasis include myoglobin and neuroglobin.

    “Hemoproteins involved in tissue oxygen homeostasis include myoglobin and neuroglobin.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [22] Rieske JS Composition, structure and function of complex III of the respiratory chain Biochim Biophys Acta 456 1976 195 247 788795 source

      Not checked in the free run.

    • cites [23] Omura T Sato R The carbon monoxide-binding pigment of liver microsomes. I. Evidence for its hemoprotein nature J Biol Chem 239 1964 2370 2378 14209971 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Energy generation by the electron transport chain relies on heme-dependent c- and b-type cytochromes of the Complex III family.

    “Energy generation by the electron transport chain relies on heme-dependent c- and b-type cytochromes of the ubiquinol–ferricytochrome c oxidoreductase (Complex III) family [22,23].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [22] Rieske JS Composition, structure and function of complex III of the respiratory chain Biochim Biophys Acta 456 1976 195 247 788795 source

      Not checked in the free run.

    • cites [23] Omura T Sato R The carbon monoxide-binding pigment of liver microsomes. I. Evidence for its hemoprotein nature J Biol Chem 239 1964 2370 2378 14209971 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Cell-free Hb abundance is thought to be very low in healthy adults, but genetic disorders, infections, and other disease states can increase free Hb concentration.

    “The abundance of cell-free Hb is thought to be very low in healthy adults, but a variety of genetic disorders, infections, and other disease states can increase the concentration of free Hb [28].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [28] Schaer DJ Buehler PW Cell-free hemoglobin and its scavenger proteins: new disease models leading the way to targeted therapies Cold Spring Harb Perspect Med 3 2013 PMC3662353 23645855 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    Organisms have evolved strategies to acquire, store, and regulate intracellular iron.

    “Therefore, organisms have evolved elaborate strategies to acquire, store, and regulate intracellular iron for heme-dependent and other iron-dependent enzymes.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Limited pathogen access to metals is an antimicrobial strategy and limits bacterial replication.

    “The limited access of pathogens to metals serves as an antimicrobial strategy and limits bacterial replication.”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [15] Cassat JE Skaar EP Iron in infection and immunity Cell Host Microbe 13 2013 509 519 23684303 PMC3676888 source

      Not checked in the free run.

    • cites [16] Hood MI Skaar EP Nutritional immunity: transition metals at the pathogen-host interface Nat Rev Microbiol 10 2012 525 537 22796883 PMC3875331 source

      Not checked in the free run.

    • cites [17] Zackular JP Chazin WJ Skaar EP Nutritional immunity: S100 proteins at the host–pathogen interface J Biol Chem 290 2015 18991 18998 26055713 PMC4521021 source

      Not checked in the free run.

    • cites [18] Juttukonda LJ Skaar EP Manganese homeostasis and utilization in pathogenic bacteria Mol Microbiol 97 2015 216 228 25898914 PMC4631260 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Nutritional immunity describes host processes that sequester iron to limit acquisition by bacterial pathogens.

    “Nutritional immunity, a concept articulated primarily by Eugene Weinberg in the 1970s, describes the processes by which humans and other organisms sequester iron to limit acquisition by bacterial pathogens [13,14].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [13] Weinberg ED Iron and susceptibility to infectious disease Science 184 1974 952 956 4596821 source

      Not checked in the free run.

    • cites [14] Weinberg ED Nutritional immunity: host's attempt to withold iron from microbial invaders JAMA 231 1975 39 41 1243565 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Heme makes up the greatest reservoir of iron in the host and serves as an iron source for many bacterial pathogens.

    “Heme makes up the greatest reservoir of iron in the host and serves as an iron source for many bacterial pathogens.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [15] Cassat JE Skaar EP Iron in infection and immunity Cell Host Microbe 13 2013 509 519 23684303 PMC3676888 source

      Not checked in the free run.

    • cites [24] Bridges KR Seligman PA Disorders of Iron Metabolism J.B Lippincott Company New York 1995

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Heme is bound by hemoproteins to serve intracellular and extracellular tasks.

    “Heme is then bound by hemoproteins to serve a variety of intracellular and extracellular tasks.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [22] Rieske JS Composition, structure and function of complex III of the respiratory chain Biochim Biophys Acta 456 1976 195 247 788795 source

      Not checked in the free run.

    • cites [23] Omura T Sato R The carbon monoxide-binding pigment of liver microsomes. I. Evidence for its hemoprotein nature J Biol Chem 239 1964 2370 2378 14209971 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisereasoning

    Eukaryotic heme synthesis is highly regulated, and heme homeostasis and sequestration are well orchestrated to prevent excess heme toxicity.

    “To prevent excess heme toxicity, eukaryotic heme synthesis is highly regulated and heme homeostasis and sequestration are well orchestrated.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [25] Everse J Hsia N The toxicities of native and modified hemoglobins Free Radic Biol Med 22 1997 1075 1099 9034247 source

      Not checked in the free run.

    • cites [26] Anzaldi LL Skaar EP Overcoming the heme paradox: heme toxicity and tolerance in bacterial pathogens Infect Immun 78 2010 4977 4989 20679437 PMC2981329 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Catalase, peroxidase, and myeloperoxidase rely on heme to catalyze hydrolysis of peroxide molecules.

    “Catalase, peroxidase, and myeloperoxidase rely on heme to catalyze the hydrolysis of peroxide molecules.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [22] Rieske JS Composition, structure and function of complex III of the respiratory chain Biochim Biophys Acta 456 1976 195 247 788795 source

      Not checked in the free run.

    • cites [23] Omura T Sato R The carbon monoxide-binding pigment of liver microsomes. I. Evidence for its hemoprotein nature J Biol Chem 239 1964 2370 2378 14209971 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    HemA produces glutamate-1-semialdehyde, which HemL converts to ALA.

    “The gluta-myl-tRNA reductase HemA produces the highly reactive intermediate glutamate-1-semialdehyde, which HemL, a glutamate-1-semialdehyde amino-mutase, converts to ALA [36,37].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [36] Hoober JK Kahn A Ash DE Gough S Kannangara CG Biosynthesis of delta-aminolevulinate in greening barley leaves. IX. Structure of the substrate, mode of gabaculine inhibition, and the catalytic mechanism of glutamate 1-semialdehyde aminotransferase Carlsb Res Commun 53 1988 3256306 source

      Not checked in the free run.

    • cites [37] Kannangara CG Gough SP Bruyant P Hoober JK Kahn A von Wettstein D tRNA(Glu) as a cofactor in delta-aminolevulinate biosynthesis: steps that regulate chlorophyll synthesis Trends Biochem Sci 13 1988 139 143 3075378 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    HemG in Gammaproteobacteria and some Alphaproteobacteria and Deltaproteobacteria uses the respiratory chain as its electron acceptor and is not dependent on oxygen.

    “HemG, in Gammaproteobacteria and some Alphaproteobactera and Deltaproteobacteria, uses the respiratory chain as its electron acceptor and is not dependent on oxygen [48].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [48] Boynton TO Daugherty LE Dailey TA Dailey HA Identification of Escherichia coli HemG as a novel, menadione-dependent flavodoxin with protoporphyrinogen oxidase activity Biochemistry 48 2009 6705 6711 19583219 PMC2749469 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Addition of heme to E. coli cell extracts reduces total HemA activity without inhibiting the purified enzyme.

    “The addition of heme to cell extracts of E. coli reduces total HemA activity, without inhibiting the activity of the purified enzyme [58,59].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [58] Jahn D Michelsen U Soll D Two glutamyl-tRNA reductase activities in Escherichia coli J Biol Chem 266 1991 2542 2548 1990004 source

      Not checked in the free run.

    • cites [59] Javor GT Febre EF Enzymatic basis of thiol-stimulated secretion of porphyrins by Escherichia coli J Bacteriol 174 1992 1072 1075 1732201 PMC206203 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    The three steps from ALA to uroporphyrinogen are well conserved and thought to be the evolutionary core of heme biosynthesis.

    “The three steps, from ALA to uroporphyrinogen, are well conserved and thought to be the evolutionary core of heme biosynthesis.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [38] Hansson M Rutberg L Schroder I Hederstedt L The Bacillus subtilis hemAXCDBL gene cluster, which encodes enzymes of the biosynthetic pathway from glutamate to uroporphyrinogen III J Bacteriol 173 1991 2590 2599 1672867 PMC207825 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Very few HemF or HemN coproporphyrinogen oxidases can be identified in Gram-positive genomes; instead, annotated HemY in these organisms functions as a coproporphyrinogen oxidase to form coproporphyrin III.

    “Very few HemF or HemN coproporphyrinogen oxidases can be identified in Gram-positive genomes; instead it has been realized that the annotated HemY in these organisms functions as a coproporphyrinogen oxidase to form coproporphyrin III [34,53].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [34] Dailey HA Gerdes S Dailey TA Burch JS Phillips JD Noncanonical coproporphyrin-dependent bacterial heme biosynthesis pathway that does not use protoporphyrin Proc Natl Acad Sci USA 112 2015 2210 2215 25646457 PMC4343137 source

      Not checked in the free run.

    • cites [53] Hansson M Gustafsson MC Kannangara CG Hederstedt L Isolated Bacillus subtilis HemY has copropor-phyrinogen III to coproporphyrin III oxidase activity Biochim Biophys Acta 1340 1997 97 104 9217019 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Regulation of HemA is typically heme-dependent, indicating that bacteria reduce synthesis of heme and its intermediates under heme-replete conditions.

    “Regulation of HemA is typically heme-dependent, indicating that bacteria reduce synthesis of heme and all intermediates in heme-replete conditions.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    During infection of heme- and Hb-replete niches, bacterial pathogens experience heme toxicity and encode systems to protect from heme toxicity.

    “During infection of host heme- and Hb-replete niches, bacterial pathogens experience heme toxicity and encode systems to protect from heme toxicity as well [33].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [33] Stauff DL Skaar EP Bacillus anthracis HssRS signalling to HrtAB regulates haem resistance during infection Mol Microbiol 72 2009 763 778 19400785 PMC2891670 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Uroporphyrinogen III can be used for synthesis of several tetrapyrrole-based cofactors.

    “Uroporphyrinogen III can be utilized for the synthesis of several tetrapyrrole-based cofactors.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [42] Hansson M Hederstedt L Cloning and characterization of the Bacillus subtilis hemEHY gene cluster, which encodes protoheme IX biosynthetic enzymes J Bacteriol 174 1992 8081 8093 1459957 PMC207547 source

      Not checked in the free run.

    • cites [43] Leeper FJ The biosynthesis of porphyrins, chlorophylls, and vitamin B12 Nat Prod Rep 4 1987 441 469 3325863 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    HemE decarboxylates four acetate side chains to methyl groups, producing coproporphyrinogen III.

    “Uroporphyrinogen III decarboxylase (HemE) decarboxylates the four acetate side chains to methyl groups, producing coproporphyrinogen III, the next step in heme synthesis [42].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [42] Hansson M Hederstedt L Cloning and characterization of the Bacillus subtilis hemEHY gene cluster, which encodes protoheme IX biosynthetic enzymes J Bacteriol 174 1992 8081 8093 1459957 PMC207547 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    HemJ is poorly characterized but is the most common protoporphyrinogen oxidase among Alphaproteobacteria and Deltaproteobacteria.

    “HemJ is poorly characterized but represents the most common protoporphyrinogen oxidase among Alphaproteobactera and Deltaproteobacteria [49].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [49] Kobayashi K Masuda T Tajima N Wada H Sato N Molecular phylogeny and intricate evolutionary history of the three isofunctional enzymes involved in the oxidation of protoporphyrinogen IX Genome Biol Evol 6 2014 2141 2155 25108393 PMC4231631 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    The contribution of the Ahb alternative heme pathway has not been demonstrated in bacterial pathogens.

    “The contribution of the Ahb alternative heme pathway has not been demonstrated in bacterial pathogens.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Ahb enzymes of some archaea and sulfur-reducing bacteria can convert siroheme to heme.

    “The Ahb enzymes of some archaea and sulfur-reducing bacteria can convert siroheme (produced from uroporphyrinogen) to heme [44,45].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [44] Bali S Lawrence AD Lobo SA Saraiva LM Golding BT Palmer DJ Molecular hijacking of siroheme for the synthesis of heme and d1 heme Proc Natl Acad Sci USA 108 2011 18260 18265 21969545 PMC3215036 source

      Not checked in the free run.

    • cites [45] Bali S Palmer DJ Schroeder S Ferguson SJ Warren MJ Recent advances in the biosynthesis of modified tetrapyrroles: the discovery of an alternative pathway for the formation of heme and heme d 1 Cell Mol Life Sci 71 2014 2837 2863 24515122 PMC11113276 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Uroporphyrinogen III can be shunted from heme synthesis and converted to precorrin-2 to synthesize vitamin B12, coenzyme F430, and siroheme.

    “Additionally, uroporphyrinogen III can be shunted from heme synthesis and converted to precorrin-2 to synthesize vitamin B12, coenzyme F430, and siroheme [43].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [43] Leeper FJ The biosynthesis of porphyrins, chlorophylls, and vitamin B12 Nat Prod Rep 4 1987 441 469 3325863 source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisenone given

    The terminal steps of the classical pathway were considered universally conserved for all heme-synthesizing organisms.

    “The terminal steps of the classical pathway were considered universally conserved for all heme synthesizing organisms.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [34] Dailey HA Gerdes S Dailey TA Burch JS Phillips JD Noncanonical coproporphyrin-dependent bacterial heme biosynthesis pathway that does not use protoporphyrin Proc Natl Acad Sci USA 112 2015 2210 2215 25646457 PMC4343137 source

      Not checked in the free run.

    • cites [52] Lobo SA Scott A Videira MA Winpenny D Gardner M Palmer MJ Staphylococcus aureus haem biosynthesis: characterisation of the enzymes involved in final steps of the pathway Mol Microbiol 97 2015 472 487 25908396 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Pseudomonas hemF and hemN are expressed anaerobically under the control of Anr and Dnr, while Anr induces expression of only hemN aerobically.

    “Similarly, Pseudomonas hemF and hemN are expressed anaerobically under the control of Anr and Dnr, while Anr induces the expression of only hemN aerobically [79].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [79] Rompf A Hungerer C Hoffmann T Lindenmeyer M Romling U Gross U Regulation of Pseudomonas aeruginosa hemF and hemN by the dual action of the redox response regulators Anr and Dnr Mol Microbiol 29 1998 985 997 9767567 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    As in B. subtilis, PerR has been implicated as a regulator of the hemEHY operon in Staphylococcus aureus; however, recent work shows major differences between B. subtilis and S. aureus PerR orthologs, making it difficult to conclude that PerR plays a role in S. aureus heme synthesis.

    “As in B. subtilis, PerR has been implicated as a regulator of the hemEHY operon in Staphylococcus aureus; yet recent work has demonstrated that major differences exist between B. subtilis and S. aureus PerR orthologs, and therefore, it is difficult to conclude that PerR plays a role in S. aureus heme synthesis [69,70].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [69] Ji CJ Kim JH Won YB Lee YE Choi TW Ju SY Staphylococcus aureus PerR Is a hypersensitive hydrogen peroxide sensor using iron-mediated histidine oxidation J Biol Chem 290 2015 20374 20386 26134568 PMC4536443 source

      Not checked in the free run.

    • cites [70] Ravcheev DA Best AA Tintle N Dejongh M Osterman AL Novichkov PS Inference of the transcriptional regulatory network in Staphylococcus aureus by integration of experimental and genomics-based evidence J Bacteriol 193 2011 3228 3240 21531804 PMC3133287 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Mutations in HemA render it resistant to heme- and protease-mediated degradation, indicating that HemA binds excess heme and that holo-HemA but not apo-HemA is a substrate for proteolytic degradation.

    “Furthermore, mutations in HemA have been described that render HemA resistant to heme- and protease-mediated degradation, indicating that HemA binds excess heme, and holo-HemA but not apo-HemA is a substrate for proteolytic degradation [62,63].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [62] Jones AM Elliott T A purified mutant HemA protein from Salmonella enterica serovar Typhimurium lacks bound heme and is defective for heme-mediated regulation in vivo FEMS Microbiol Lett 307 2010 41 47 20412302 source

      Not checked in the free run.

    • cites [63] Wang L Wilson S Elliott T A mutant HemA protein with positive charge close to the N terminus is stabilized against heme-regulated proteolysis in Salmonella typhimurium J Bacteriol 181 1999 6033 6041 10498716 PMC103631 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Two promoters exist upstream of hemA in Pseudomonas aeruginosa, and these promoters contain binding sites for Anr, Dnr, IHF, and NarL.

    “Two promoters exist upstream of hemA in the Gram-negative pathogen Pseudomonas aeruginosa, and these promoters contain binding sites for the regulators Anr (oxygen sensing), Dnr (redox regulator), IHF (integration host factor), and NarL (nitrate regulator) [66,67].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [66] Krieger R Rompf A Schobert M Jahn D The Pseudomonas aeruginosa hemA promoterisregulatedby Anr, Dnr, NarL and Integration Host Factor Mol Gen Genomics 267 2002 409 417 12073043 source

      Not checked in the free run.

    • cites [67] Hungerer C Troup B Romling U Jahn D Regulation of the hemA gene during 5-aminolevulinic acid formation in Pseudomonas aeruginosa J Bacteriol 177 1995 1435 1443 7883699 PMC176757 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Excess heme results in proteolytic degradation of HemA in Salmonella, suggesting that HemA might bind excess heme.

    “This was explained by the observation that excess heme results in the proteolytic degradation of HemA in Salmonella, suggesting that HemA might bind excess heme [60].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [60] Wang LY Brown L Elliott M Elliott T Regulation of heme biosynthesis in Salmonella typhimurium: activity of glutamyl-tRNA reductase (HemA) is greatly elevated during heme limitation by a mechanism which increases abundance of the protein J Bacteriol 179 1997 2907 2914 9139907 PMC179053 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In B. subtilis, hemEHY is induced anaerobically and hemAXCBL is induced by peroxide through de-repression of PerR.

    “In B. subtilis, hemEHY is induced anaerobically and hemAXCBL is induced by peroxide through de-repression of PerR [38,68].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [38] Hansson M Rutberg L Schroder I Hederstedt L The Bacillus subtilis hemAXCDBL gene cluster, which encodes enzymes of the biosynthetic pathway from glutamate to uroporphyrinogen III J Bacteriol 173 1991 2590 2599 1672867 PMC207825 source

      Not checked in the free run.

    • cites [68] Ye RW Tao W Bedzyk L Young T Chen M Li L Global gene expression profiles of Bacillus subtilis grown under anaerobic conditions J Bacteriol 182 2000 4458 4465 10913079 PMC94617 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Therefore, hemA expression is induced in the presence of oxygen or when oxygen is lacking but an alternative electron acceptor such as nitrate is present for heme-dependent respiration.

    “Therefore, hemA expression is induced in the presence of oxygen or when oxygen is lacking but an alternative electron acceptor such as nitrate is present for utilization of heme-dependent respiration.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Homologs of B. subtilis HemX exist in multiple Gram-positive pathogens, but the function of HemX and HemA regulation has yet to be detailed.

    “Homologs of B. subtilis HemX exist in multiple Gram-positive pathogens; however, the function of HemX and HemA regulation has yet to be detailed.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [38] Hansson M Rutberg L Schroder I Hederstedt L The Bacillus subtilis hemAXCDBL gene cluster, which encodes enzymes of the biosynthetic pathway from glutamate to uroporphyrinogen III J Bacteriol 173 1991 2590 2599 1672867 PMC207825 source

      Not checked in the free run.

    • cites [65] Schroder I Johansson P Rutberg L Hederstedt L The hemX gene of the Bacillus subtilis hemAXCDBL operon encodes a membrane protein, negatively affecting the steady-state cellular concentration of HemA (glutamyl-tRNA reductase) Microbiology 140 1994 731 740 8012594 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    For S. aureus, heme synthesis and acquisition are vital during infection, but the regulation of heme synthesis is unknown.

    “For S. aureus, in which heme synthesis and acquisition are vital during infection, the regulation of heme synthesis is unknown.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    This results in accessible free heme, heme bound by hemopexin, free Hb, and Hb bound by haptoglobin to form the Hp-Hb complex.

    “This results in accessible free heme, heme bound by hemopexin (Hx), free Hb (Hb), and Hb bound by Hp to form the Hp–Hbcomplex.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    For S. aureus, reliance on heme acquisition during infection has been well established, and heme biosynthesis is vital to cause disease in murine models of infection.

    “For S. aureus, whose reliance on heme acquisition during infection has been well established, it is now clear that heme biosynthesis is vital to cause disease in murine models of infection [84–86].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [84] Skaar EP Humayun M Bae T DeBord KL Schneewind O Iron-source preference of Staphylococcus aureus infections Science 305 2004 1626 1628 15361626 source

      Not checked in the free run.

    • cites [85] Pishchany G Sheldon JR Dickson CF Alam MT Read TD Gell DA IsdB-dependent hemoglobin binding is required for acquisition of heme by Staphylococcus aureus J Infect Dis 209 2014 1764 1772 24338348 PMC4038968 source

      Not checked in the free run.

    • cites [86] Pishchany G McCoy AL Torres VJ Krause JC Crowe JE Jr Fabry ME Specificity for human hemoglobin enhances Staphylococcus aureus infection Cell Host Microbe 8 2010 544 550 21147468 PMC3032424 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    For other pathogens, the contribution of heme synthesis to disease is still unclear, but whole-genome in vivo fitness experiments suggest many bacterial pathogens rely on heme biosynthesis to cause disease.

    “For other pathogens, the contribution of heme synthesis to disease is still unclear, but whole-genome in vivo fitness experiments like transposon-sequencing suggest many bacterial pathogens rely on heme biosynthesis to cause disease”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Heme acquired from the host is used fully intact or degraded to liberate heme-iron, and both processes are important during bacterial pathogenesis.

    “Heme acquired from the host is used fully intact or degraded to liberate heme-iron and both processes are important during bacterial pathogenesis.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [115] Skaar EP Gaspar AH Schneewind O IsdG and IsdI, heme-degrading enzymes in the cytoplasm of Staphylococcus aureus J Biol Chem 279 2004 436 443 14570922 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Therefore, like S. aureus, host heme utilization is insufficient and synthesis is required for full virulence.

    “Therefore, like S. aureus, host heme utilization is insufficient and synthesis is required for full virulence.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    The contribution of heme synthesis to the pathogenesis of bacterial pathogens is largely understudied.

    “However, the contribution of heme synthesis to the pathogenesis of bacterial pathogens is largely understudied.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Despite reduced virulence, SCVs are generally more resistant to antibiotics and oxidative stress, more equipped to evade the immune system by living intracellularly, and are likely the etiological agent of persistent staphylococcal infections.

    “Despite their reduced virulence, SCVs are generally more resistant to antibiotics and oxidative stress, more equipped to evade the immune system by living intracellularly, and are likely the etiological agent of persistent staphylococcal infections [89–92]”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [89] von Eiff C Heilmann C Proctor RA Woltz C Peters G Gotz F A site-directed Staphylococcus aureus hemB mutant is a small-colony variant which persists intracellularly J Bacteriol 179 1997 4706 4712 9244256 PMC179315 source

      Not checked in the free run.

    • cites [90] Balwit JM van Langevelde P Vann JM Proctor RA Gentamicin-resistant menadione and hemin auxotrophic Staphylococcus aureus persist within cultured endothelial cells J Infect Dis 170 1994 1033 1037 7930701 source

      Not checked in the free run.

    • cites [91] Painter KL Strange E Parkhill J Bamford KB Armstrong-James D Edwards AM Staphylococcus aureus adapts to oxidative stress by producing H2O2-resistant small-colony variants via the SOS response Infect Immun 83 2015 1830 1844 25690100 PMC4399076 source

      Not checked in the free run.

    • cites [92] Sadowska B Bonar A von Eiff C Proctor RA Chmiela M Rudnicka W Characteristics of Staphylococcus aureus, isolated from airways of cystic fibrosis patients, and their small colony variants FEMS Immunol Med Microbiol 32 2002 191 197 11934563 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The Isd system enables utilization of free heme, or heme bound to Hb and Hp-Hb complexes.

    “The Isd system enables utilization of free heme, or heme bound to Hb and Hp–Hb complexes.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [102] Mazmanian SK Skaar EP Gaspar AH Humayun M Gornicki P Jelenska J Passage of heme-iron across the envelope of Staphylococcus aureus Science 299 2003 906 909 12574635 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Inactivation of hemA renders S. aureus heme deficient and causes the small-colony variant phenotype.

    “Inactivation of hemA, which renders S. aureus heme deficient, causes the small-colony variant (SCV) phenotype [87].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [87] Hammer ND Reniere ML Cassat JE Zhang Y Hirsch AO Hood MI Two heme-dependent terminal oxidases power Staphylococcus aureus organ-specific colonization of the vertebrate host mBio 4 2013 PMC3735196 23900169 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    These data demonstrate that for S. aureus, heme acquisition is insufficient to support organ colonization and therefore heme biosynthesis is critical to pathogenesis.

    “These data demonstrate that for S. aureus, heme acquisition is insufficient to support organ colonization and therefore heme biosynthesis is critical to pathogenesis.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Small molecules have been described that modulate heme synthesis in vivo, and in vitro inhibitors of S. aureus HemY have recently been reported, suggesting that Gram-positive heme synthesis is an attractive drug target.

    “Small molecules have been described that modulate heme synthesis in vivo, while in vitro inhibitors of S. aureus HemY have recently been reported, suggesting that Gram-positive heme synthesis is an attractive drug target [52,99,100].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [52] Lobo SA Scott A Videira MA Winpenny D Gardner M Palmer MJ Staphylococcus aureus haem biosynthesis: characterisation of the enzymes involved in final steps of the pathway Mol Microbiol 97 2015 472 487 25908396 source

      Not checked in the free run.

    • cites [99] Mike LA Dutter BF Stauff DL Moore JL Vitko NP Aranmolate O Activation of heme biosynthesis by a small molecule that is toxic to fermenting Staphylococcus aureus Proc Natl Acad Sci USA 110 2013 9206 8211 PMC3657828 23630262 source

      Not checked in the free run.

    • cites [100] Dutter BF Mike LA Reid PR Chong KM Ramos-Hunter SJ Skaar EP Decoupling activation of heme biosynthesis from anaerobic toxicity in a molecule active in Staphylococcus aureus ACS Chem Biol 2016 PMID: 26890615, Epub ahead of print http://dx.doi.org/10.1021/acschembio.5b00934 PMC5117894 26890615 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    S. aureus encodes an iron-regulated Sortase B for which IsdC is the only substrate, and SrtB attaches IsdC to peptidoglycan such that IsdC is not surface exposed but buried in the cell wall, which is 15-30 nm thick.

    “S. aureus encodes an iron-regulated Sortase B (SrtB) for which IsdC is the only substrate, and SrtB attaches IsdC to peptidoglycan in such a way that IsdC is not surface exposed but rather buried in the cell wall, which is 15–30 nm thick [112,113].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [112] Mazmanian SK Ton-That H Su K Schneewind O An iron-regulated sortase anchors a class of surface protein during Staphylococcus aureus pathogenesis Proc Natl Acad Sci USA 99 2002 2293 2298 11830639 PMC122358 source

      Not checked in the free run.

    • cites [113] Beveridge J Ultrastructure of Gram-positive cell walls Fishetti VA Novick RP Feretti JJ Portnoy DA Rood JI Gram-Positive Pathogens second ASM Press Washington, DC 2000 3 10

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    IsdB contains two NEAT domains; NEAT1 binds Hb and Hb-Hp but not Hp, and N2 binds heme; IsdB is believed to be the primary Hb-binding protein.

    “IsdB contains two NEAT domains, NEAT1 (N1) binds Hb and Hb–Hp, but not Hp and N2 binds heme; as such IsdB is believed to be the primary Hb-binding protein [85,107,108].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [85] Pishchany G Sheldon JR Dickson CF Alam MT Read TD Gell DA IsdB-dependent hemoglobin binding is required for acquisition of heme by Staphylococcus aureus J Infect Dis 209 2014 1764 1772 24338348 PMC4038968 source

      Not checked in the free run.

    • cites [107] Fonner BA Tripet BP Eilers BJ Stanisich J Sullivan-Springhetti RK Moore R Solution structure and molecular determinants of hemoglobin binding of the first NEAT domain of IsdB in Staphylococcus aureus Biochemistry 53 2014 3922 3933 24871270 PMC4072347 source

      Not checked in the free run.

    • cites [108] Torres VJ Pishchany G Humayun M Schneewind O Skaar EP Staphylococcus aureus IsdB is a hemoglobin receptor required for heme iron utilization J Bacteriol 188 2006 8421 8429 17041042 PMC1698231 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Similarly, IsdH-N1 and N2 bind Hb and Hp, and IsdH-N3 extracts heme.

    “Similarly, IsdHN1 and N2 bind Hb and Hp, and IsdH-N3 extracts the heme.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [111] Muryoi N Tiedemann MT Pluym M Cheung J Heinrichs DE Stillman MJ Demonstration of the iron-regulated surface determinant (Isd) heme transfer pathway in Staphylococcus aureus J Biol Chem 283 2008 28125 28136 18676371 PMC2661384 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    IsdG and IsdI are structurally similar and are the first described members of the Isd heme oxygenase family, which catabolizes heme to staphylobilin instead of biliverdin.

    “IsdG and IsdI are structurally similar and are the first described members of the Isd heme oxygenase family, which catabolizes heme to staphylobilin instead of biliverdin [117–119].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [117] Reniere ML Ukpabi GN Harry SR Stec DF Krull R Wright DW The IsdG-family of haem oxygenases degrades haem to a novel chromophore Mol Microbiol 75 2010 1529 1538 20180905 PMC3800195 source

      Not checked in the free run.

    • cites [118] Lee WC Reniere ML Skaar EP Murphy ME Ruffling of metalloporphyrins bound to IsdG and IsdI, two hemed-egrading enzymes in Staphylococcus aureus J Biol Chem 283 2008 30957 30963 18713745 PMC2576546 source

      Not checked in the free run.

    • cites [119] Wu R Skaar EP Zhang R Joachimiak G Gornicki P Schneewind O Staphylococcus aureus IsdG and IsdI, heme-degrading enzymes with structural similarity to monooxygenases J Biol Chem 280 2005 2840 2846 15520015 PMC2792019 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Upon import, heme is incorporated into staphylococcal proteins or degraded.

    “Upon import, heme is incorporated into staphylococcal proteins or degraded.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [115] Skaar EP Gaspar AH Schneewind O IsdG and IsdI, heme-degrading enzymes in the cytoplasm of Staphylococcus aureus J Biol Chem 279 2004 436 443 14570922 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    IsdG and IsdI are required for growth using heme as a sole iron source and are expressed during infection.

    “IsdG and IsdI are required for growth using heme as a sole iron source and are expressed during infection [115,120].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [115] Skaar EP Gaspar AH Schneewind O IsdG and IsdI, heme-degrading enzymes in the cytoplasm of Staphylococcus aureus J Biol Chem 279 2004 436 443 14570922 source

      Not checked in the free run.

    • cites [120] Reniere ML Skaar EP Staphylococcus aureus haem oxygenases are differentially regulated by iron and haem Mol Microbiol 69 2008 1304 1315 18643935 PMC2597461 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    IsdA is partially surface exposed and contains a single heme-binding NEAT domain.

    “IsdA, which is partially surface exposed, contains a single heme-binding NEAT domain [102].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [102] Mazmanian SK Skaar EP Gaspar AH Humayun M Gornicki P Jelenska J Passage of heme-iron across the envelope of Staphylococcus aureus Science 299 2003 906 909 12574635 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The current model, supported by strong structural evidence, suggests that IsdB-N1 binds Hb and IsdB-N2 extracts heme.

    “The current model (Fig. 2), supported by strong structural evidence, suggests that IsdB-N1 binds Hb, and IsdB-N2 extracts heme [111].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [111] Muryoi N Tiedemann MT Pluym M Cheung J Heinrichs DE Stillman MJ Demonstration of the iron-regulated surface determinant (Isd) heme transfer pathway in Staphylococcus aureus J Biol Chem 283 2008 28125 28136 18676371 PMC2661384 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    NEAT domains are 120-125 amino acid domains that constitute a conserved eight-stranded β-sandwich fold.

    “The NEAT domains are 120–125 aa domains that constitute a conserved eight-stranded β-sandwich fold [104,105].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [104] Grigg JC Vermeiren CL Heinrichs DE Murphy ME Haem recognition by a Staphylococcus aureus NEAT domain Mol Microbiol 63 2007 139 149 17229211 source

      Not checked in the free run.

    • cites [105] Sharp KH Schneider S Cockayne A Paoli M Crystal structure of the heme-IsdC complex, the central conduit of the Isd iron/heme uptake system in Staphylococcus aureus J Biol Chem 282 2007 10625 10631 17287214 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Exogenous heme accumulates in the membrane and is capable of complementing the growth of heme-deficient mutants.

    “Exogenous heme accumulates in the membrane and is also capable of complementing the growth of heme-deficient mutants [84].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [84] Skaar EP Humayun M Bae T DeBord KL Schneewind O Iron-source preference of Staphylococcus aureus infections Science 305 2004 1626 1628 15361626 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Further regulation of the heme oxygenases exists; IsdG abundance increases in the presence of heme and IsdG half-life is increased when heme-bound.

    “Further regulation of the heme oxygenases exists; IsdG abundance increases in the presence of heme and IsdG half-life is increased when heme-bound [120].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [120] Reniere ML Skaar EP Staphylococcus aureus haem oxygenases are differentially regulated by iron and haem Mol Microbiol 69 2008 1304 1315 18643935 PMC2597461 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Heme is transferred either directly to IsdC or shuttled via IsdA to IsdC.

    “The heme is then transferred either directly to IsdC or shuttled via IsdA to IsdC.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [111] Muryoi N Tiedemann MT Pluym M Cheung J Heinrichs DE Stillman MJ Demonstration of the iron-regulated surface determinant (Isd) heme transfer pathway in Staphylococcus aureus J Biol Chem 283 2008 28125 28136 18676371 PMC2661384 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    IsdH contains three NEAT domains; N1 and N2 bind both Hb and Hp, and N3 binds heme.

    “IsdH contains three NEAT domains, N1 and N2 bind both Hb and Hp, andN3bindsheme [109,110].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [109] Dryla A Gelbmann D Von Gabain A Nagy E Identification of a novel iron regulated staphylococcal surface protein with haptoglobin-haemoglobin binding activity Mol Microbiol 49 2003 37 53 12823809 source

      Not checked in the free run.

    • cites [110] Pilpa RM Robson SA Villareal VA Wong ML Phillips M Clubb RT Functionally distinct NEAT (NEAr Transporter) domains within the Staphylococcus aureus IsdH/HarA protein extract heme from methemoglobin J Biol Chem 284 2009 1166 1176 18984582 PMC2613621 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A guinea pig infection model demonstrated that ΔisdCX1X2 was as virulent as wild type, yet these proteins are expressed during infection.

    “A guinea pig infection model demonstrated that ΔisdCX1X2 was as virulent as wild type, yet these proteins are expressed during infection [134].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [134] Gat O Zaide G Inbar I Grosfeld H Chitlaru T Levy H Characterization of Bacillus anthracis iron-regulated surface determinant (Isd) proteins containing NEAT domains Mol Microbiol 70 2008 983 999 18826411 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    IsdX1 contains one NEAT domain, while IsdX2 contains five NEAT domains; both are secreted past the cell wall because they lack sortase signals or membrane-spanning domains.

    “IsdX1 contains one NEAT domain, while IsdX2 contains five NEAT domains; both are secreted past the cell wall as they lack sortase signals or membrane spanning domains [125].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [125] Maresso AW Garufi G Schneewind O Bacillus anthracis secretes proteins that mediate heme acquisition from hemoglobin PLoS Pathog 4 2008 e1000132 18725935 PMC2515342 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    B. anthracis encodes other NEAT-containing proteins; Hal contains a single NEAT domain and leucine-rich repeats, which extract heme from Hb.

    “B. anthracis also encodes other NEAT contain proteins; Hal contains a single NEAT domain and leucine-rich repeats, which extract heme from Hb [130].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [130] Balderas MA Nobles CL Honsa ES Alicki ER Maresso AW Hal Is a Bacillus anthracis heme acquisition protein J Bacteriol 194 2012 5513 5521 22865843 PMC3458686 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    IsdX1 and IsdX2 are the first described Gram-positive hemophores and bind heme, Hb, and methemoglobin.

    “These are the first described Gram-positive hemophores and bind heme, Hb, and methemoglobin [125– 129].”
    Quote in the paperNot a substantial claim0 of 5 sources checked
    • cites [125] Maresso AW Garufi G Schneewind O Bacillus anthracis secretes proteins that mediate heme acquisition from hemoglobin PLoS Pathog 4 2008 e1000132 18725935 PMC2515342 source

      Not checked in the free run.

    • cites [126] Fabian M Solomaha E Olson JS Maresso AW Heme transfer to the bacterial cell envelope occurs via a secreted hemophore in the Gram-positive pathogen Bacillus anthracis J Biol Chem 284 2009 32138 32146 19759022 PMC2797284 source

      Not checked in the free run.

    • cites [127] Honsa ES Fabian M Cardenas AM Olson JS Maresso AW The five near-iron transporter (NEAT) domain anthrax hemophore, IsdX2, scavenges heme from hemoglobin and transfers heme to the surface protein IsdC J Biol Chem 286 2011 33652 33660 21808055 PMC3190864 source

      Not checked in the free run.

    • cites [128] Maresso AW Chapa TJ Schneewind O Surface protein IsdC and Sortase B are required for heme-iron scavenging of Bacillus anthracis J Bacteriol 188 2006 8145 8152 17012401 PMC1698196 source

      Not checked in the free run.

    • cites [129] Honsa ES Owens CP Goulding CW Maresso AW The near-iron transporter (NEAT) domains of the anthrax hemophore IsdX2 require a critical glutamine to extract heme from methemoglobin J Biol Chem 288 2013 8479 8490 23364793 PMC3605663 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The current proposed model is that IsdX1 is secreted, binds heme, and transfers heme to wall-anchored IsdC.

    “The current proposed model (Fig. 2) is that IsdX1 is secreted, binds heme, and transfers heme to wall-anchored IsdC.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [125] Maresso AW Garufi G Schneewind O Bacillus anthracis secretes proteins that mediate heme acquisition from hemoglobin PLoS Pathog 4 2008 e1000132 18725935 PMC2515342 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    B. anthracis encodes a heme uptake system that shares the core of the S. aureus Isd but has additional unique proteins.

    “B. anthracis encodes a heme uptake system that shares the core of the S. aureus Isd, but with additional unique proteins.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [125] Maresso AW Garufi G Schneewind O Bacillus anthracis secretes proteins that mediate heme acquisition from hemoglobin PLoS Pathog 4 2008 e1000132 18725935 PMC2515342 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    The diversity of heme and Hb-binding proteins relative to S. aureus may be the result of the greater variety of environmental niches that germinant and sporulent B. anthracis inhabits.

    “The diversity of heme and Hb-binding proteins relative to S. aureus may be the result of the greater variety of environmental niches that germinant and sporulent B. anthracis inhabits.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    It is likely that the IsdX1/X2 hemophores, BslK, and Hal are partially redundant, and a mutant lacking all four proteins would be highly defective in causing anthrax.

    “It is likely that the IsdX1/X2 hemophores, BslK, and Hal are partially redundant, and a mutant lacking all four proteins would be highly defective in causing anthrax.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    BslK is non-covalently attached to the cell wall and transfers heme to IsdC.

    “A second, recently described NEAT protein is BslK, which is non-covalently attached to the cell wall and transfers heme to IsdC [132].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [132] Tarlovsky Y Fabian M Solomaha E Honsa E Olson JS Maresso AW A Bacillus anthracis S-layer homology protein that binds heme and mediates heme delivery to IsdC J Bacteriol 192 2010 3503 3511 20435727 PMC2897652 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Heme is the preferred iron source during systemic infection, in part because a heme-responsive transcriptional regulator activates iron siderophore synthesis only when heme-iron is unavailable.

    “Heme is the preferred iron-source during systemic infection, in part because a heme-responsive transcriptional regulator activates iron siderophore synthesis only when heme-iron is unavailable [84,122].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [84] Skaar EP Humayun M Bae T DeBord KL Schneewind O Iron-source preference of Staphylococcus aureus infections Science 305 2004 1626 1628 15361626 source

      Not checked in the free run.

    • cites [122] Laakso HA Marolda CL Pinter TB Stillman MJ Heinrichs DE A heme-responsive regulator controls synthesis of Staphyloferrin B in Staphylococcus aureus J Biol Chem 291 2016 29 40 26534960 PMC4697164 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    IsdX2 can bind free heme, accept heme from IsdX1, and transfer heme to IsdC.

    “IsdX2 can bind free heme, accept heme from IsdX1, and transfer heme to IsdC.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [125] Maresso AW Garufi G Schneewind O Bacillus anthracis secretes proteins that mediate heme acquisition from hemoglobin PLoS Pathog 4 2008 e1000132 18725935 PMC2515342 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Mutants lacking components of the Isd system are highly defective in pathogenesis, highlighting the importance of heme acquisition to staphylococcal disease.

    “Mutants lacking components of the Isd system are highly defective inpathogenesis, highlighting the importance of heme acquisition to staphylo-coccal disease [84–86,108,120,123,124].”
    Quote in the paperSubstantial claim0 of 7 sources checked
    • cites [84] Skaar EP Humayun M Bae T DeBord KL Schneewind O Iron-source preference of Staphylococcus aureus infections Science 305 2004 1626 1628 15361626 source

      Not checked in the free run.

    • cites [85] Pishchany G Sheldon JR Dickson CF Alam MT Read TD Gell DA IsdB-dependent hemoglobin binding is required for acquisition of heme by Staphylococcus aureus J Infect Dis 209 2014 1764 1772 24338348 PMC4038968 source

      Not checked in the free run.

    • cites [86] Pishchany G McCoy AL Torres VJ Krause JC Crowe JE Jr Fabry ME Specificity for human hemoglobin enhances Staphylococcus aureus infection Cell Host Microbe 8 2010 544 550 21147468 PMC3032424 source

      Not checked in the free run.

    • cites [108] Torres VJ Pishchany G Humayun M Schneewind O Skaar EP Staphylococcus aureus IsdB is a hemoglobin receptor required for heme iron utilization J Bacteriol 188 2006 8421 8429 17041042 PMC1698231 source

      Not checked in the free run.

    • cites [120] Reniere ML Skaar EP Staphylococcus aureus haem oxygenases are differentially regulated by iron and haem Mol Microbiol 69 2008 1304 1315 18643935 PMC2597461 source

      Not checked in the free run.

    • cites [123] Visai L Yanagisawa N Josefsson E Tarkowski A Pezzali I Rooijakkers SH Immune evasion by Staphylococcus aureus conferred by iron-regulated surface determinant protein IsdH Microbiology 155 2009 667 679 19246738 source

      Not checked in the free run.

    • cites [124] Cheng AG Kim HK Burts ML Krausz T Schneewind O Missiakas DM Genetic requirements for Staphylococcus aureus abscess formation and persistence in host tissues FASEB J 23 2009 3393 3404 19525403 PMC2747682 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In addition to heme, HtaA can acquire heme from Hb and transfer heme to HtaB, suggesting a heme shuttle from HtaA to HtaB to HmuT; HmuT is a surface-anchored lipoprotein that then transfers heme to the cognate ABC transporter HmuUV.

    “In addition to heme, HtaA can acquire heme from Hb and transfer heme to HtaB, suggesting a heme shuttle from HtaA toHtaB toHmuT; HmuT isa surface-anchored lipoprotein, which then transfers heme to the cognate ABC transporter HmuUV [148].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [148] Allen CE Schmitt MP Novel hemin binding domains in the Corynebacterium diphtheriae HtaA protein interact with hemoglobin and are critical for heme iron utilization by HtaA J Bacteriol 193 2011 5374 5385 21803991 PMC3187408 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    It appears that these heme-binding proteins serve redundant functions, and a mutant lacking both HtaB and ChtB is deficient at utilizing Hb as an iron source.

    “It appears that these heme-binding proteins serve redundant functions, and as such, a mutant lacking both HtaB and ChtB is deficient at utilizing Hb as an iron source [152].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [152] Allen CE Burgos JM Schmitt MP Analysis of novel iron-regulated, surface-anchored hemin-binding proteins in Corynebacterium diphtheriae J Bacteriol 195 2013 2852 2863 23585541 PMC3697262 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The current model for Hp-Hb heme acquisition involves binding of Hp-Hb by a combination of HtaA and ChtA or ChtC, heme extraction either actively or passively, and transfer to HtaB, HmuT, and HmuUV.

    “The current model (Fig. 2) for Hp–Hb heme acquisition involves binding of Hp–Hb by a combination of HtaA and ChtA or ChtC, heme extraction either actively or passively, and transfer to HtaB, HmuT, and HmuUV [153].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [153] Allen CE Schmitt MP Utilization of host iron sources by Corynebacterium diphtheriae: multiple hemoglobin-binding proteins are essential for the use of iron from the hemoglobin– haptoglobin complex J Bacteriol 197 2015 553 562 25404705 PMC4285985 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    DtxR activates the expression of Diphtheria Toxin as well as HmuTUV and HtaABC.

    “DtxR is the Diphtheria Toxin regulator which activates the expression of Diphtheria Toxin as well as HmuTUV and HtaABC [150,151].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [150] Kunkle CA Schmitt MP Analysis of a DtxR-regulated iron transport and siderophore biosynthesis gene cluster in Corynebacterium diphtheriae J Bacteriol 187 2005 422 433 15629913 PMC543566 source

      Not checked in the free run.

    • cites [151] Kunkle CA Schmitt MP Analysis of the Corynebacterium diphtheriae DtxR regulon: identification of a putative siderophore synthesis and transport system that is similar to the Yersinia high-pathogenicity island-encoded yersiniabactin synthesis and uptake system J Bacteriol 185 2003 6826 6840 14617647 PMC262719 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    This results in surface exposure of HtaA and HtaB, which both bind heme.

    “This results in surface exposure of HtaA and HtaB, which both bind heme.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Adjacent to this locus are the genes htaB and htaC.

    “Adjacent to this locus are the genes htaB and htaC.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [147] Allen CE Schmitt MP HtaA is an iron-regulated hemin binding protein involved in the utilization of heme iron in Corynebacterium diphtheriae J Bacteriol 191 2009 2638 2648 19201805 PMC2668399 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Therefore, Gram-negative heme uptake systems consist of outer-membrane receptors that either bind heme and hemoproteins directly, or bind heme-bound secreted hemophores.

    “Therefore, Gram-negative heme uptake systems consist of outer-membrane receptors that either bind heme and hemoproteins directly, or bind heme-bound secreted hemophores.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Like HtaAB, ChtAB and CirAChtC are surface exposed, and ChtAB and ChtC bind heme and Hb.

    “Like HtaAB, ChtAB and CirAChtC are surface exposed and ChtAB and ChtC bind heme and Hb.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [152] Allen CE Burgos JM Schmitt MP Analysis of novel iron-regulated, surface-anchored hemin-binding proteins in Corynebacterium diphtheriae J Bacteriol 195 2013 2852 2863 23585541 PMC3697262 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    P. aeruginosa encodes direct heme uptake and hemophore systems at the outer membrane, H. influenzae uses a hemophore uptake system, and N. meningitidis uses a unique bipartite receptor for heme acquisition from host hemoproteins.

    “The versatile opportunistic pathogen P. aeruginosa encodes direct heme uptake and hemophore systems at the outer membrane, H. influenzae uses a hemophore uptake system, and Neisseria meningitidis uses a unique bipartite receptor for heme acquisition from host hemoproteins .”
    Quote in the paperNot a substantial claim0 of 6 sources checked
    • cites [154] Noinaj N Guillier M Barnard TJ Buchanan SK TonB-dependent transporters: regulation, structure, and function Annu Rev Microbiol 64 2010 43 60 20420522 PMC3108441 source

      Not checked in the free run.

    • cites [155] Letoffe S Nato F Goldberg ME Wandersman C Interactions of HasA, a bacterial haemophore, with haemoglobin and with its outer membrane receptor HasR Mol Microbiol 33 1999 546 555 10417645 source

      Not checked in the free run.

    • cites [156] Letoffe S Deniau C Wolff N Dassa E Delepelaire P Lecroisey A Haemophore-mediated bacterial haem transport: evidence for a common or overlapping site for haem-free and haem-loaded haemophore on its specific outer membrane receptor Mol Microbiol 41 2001 439 450 11489129 source

      Not checked in the free run.

    • cites [157] Smith AD Wilks A Differential contributions of the outer membrane receptors PhuR and HasR to heme acquisition in Pseudomonas aeruginosa J Biol Chem 290 2015 7756 7766 25616666 PMC4367277 source

      Not checked in the free run.

    • cites [158] Oglesby-Sherrouse AG Vasil ML Characterization of a heme-regulated non-coding RNA encoded by the prrF locus of Pseudomonas aeruginosa PLoS One 5 2010 e9930 20386693 PMC2851614 source

      Not checked in the free run.

    • cites [159] Reinhart AA Powell DA Nguyen AT O'Neill M Djapgne L Wilks A The prrF-encoded small regulatory RNAs are required for iron homeostasis and virulence of Pseudomonas aeruginosa Infect Immun 83 2015 863 875 25510881 PMC4333466 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    HmuO was discovered and described first, and then HmuTUV was discovered for the ability of a plasmid encoding hmuTUV to complement a Corynebacterium ulcerans strain that cannot grow on Hb as a sole iron source.

    “The associated heme oxygenase, HmuO, was discovered and described first, and then HmuTUV was discovered for the ability of a plasmid encoding hmuTUV to complement a Corynebacterium ulcerans strain that cannot grow on Hb as a sole iron source [144,145].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [144] Schmitt MP Utilization of host iron sources by Coryne-bacterium diphtheriae: identification of a gene whose product is homologous to eukaryotic heme oxygenases and is required for acquisition of iron from heme and hemoglobin J Bacteriol 179 1997 838 845 9006041 PMC178768 source

      Not checked in the free run.

    • cites [145] Drazek ES Hammack CA Schmitt MP Corynebacterium diphtheriae genes required for acquisition of iron from haemin and haemoglobin are homologous to ABC haemin transporters Mol Microbiol 36 2000 68 84 10760164 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    HtaA isolated from cell culture is unable to complement the growth of an htaA mutant, suggesting that surface-bound HtaA may serve as a heme receptor and secreted HtaA may serve as a hemophore.

    “HtaA isolated from cell culture is unable to complement the growth of an htaA mutant, suggesting that surface bound HtaA may serve as a heme receptor and secreted HtaA may serve as a hemophore [147,148].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [147] Allen CE Schmitt MP HtaA is an iron-regulated hemin binding protein involved in the utilization of heme iron in Corynebacterium diphtheriae J Bacteriol 191 2009 2638 2648 19201805 PMC2668399 source

      Not checked in the free run.

    • cites [148] Allen CE Schmitt MP Novel hemin binding domains in the Corynebacterium diphtheriae HtaA protein interact with hemoglobin and are critical for heme iron utilization by HtaA J Bacteriol 193 2011 5374 5385 21803991 PMC3187408 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    While Isd NEAT domains rely on tyrosine alone as the axial ligand for heme binding, HmuT relies on an N-terminal histidine and a C-terminal tyrosine to coordinate heme.

    “While the Isd NEAT domains rely on tyrosine alone as the axial ligand for heme binding, HmuT relies on an N-terminal histidine and a C-terminal tyrosine to coordinate heme [149].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [149] Draganova EB Akbas N Adrian SA Lukat-Rodgers GS Collins DP Dawson JH Heme binding by Corynebacterium diphtheriae HmuT: function and heme environment Biochemistry 54 2015 6598 6609 26478504 PMC4943319 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    ChtA and ChtC are both capable of binding Hp-Hb for heme extraction, and acquisition of heme from Hp-Hb requires HtaA.

    “Recently, it has been shown that ChtA and ChtC are both capable of binding Hp–Hb for heme extraction, and acquisition of heme from Hp–Hb requires HtaA [153].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [153] Allen CE Schmitt MP Utilization of host iron sources by Corynebacterium diphtheriae: multiple hemoglobin-binding proteins are essential for the use of iron from the hemoglobin– haptoglobin complex J Bacteriol 197 2015 553 562 25404705 PMC4285985 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Heme then transits the periplasm and is brought into the cell via ABC transporters at the inner membrane.

    “Heme then transits the periplasm and is brought into the cell via ABC transporters at the inner membrane.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [154] Noinaj N Guillier M Barnard TJ Buchanan SK TonB-dependent transporters: regulation, structure, and function Annu Rev Microbiol 64 2010 43 60 20420522 PMC3108441 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Data from the orthologous HasA hemophore of Serratia marcescens suggest that HasA binds Hb and extracts heme, then HasA transfers heme to HasR.

    “Data from the orthologous HasA hemophore of Serratia marcescens suggest that HasA binds Hb and extracts heme, then HasA transfers heme to HasR [155,156].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [155] Letoffe S Nato F Goldberg ME Wandersman C Interactions of HasA, a bacterial haemophore, with haemoglobin and with its outer membrane receptor HasR Mol Microbiol 33 1999 546 555 10417645 source

      Not checked in the free run.

    • cites [156] Letoffe S Deniau C Wolff N Dassa E Delepelaire P Lecroisey A Haemophore-mediated bacterial haem transport: evidence for a common or overlapping site for haem-free and haem-loaded haemophore on its specific outer membrane receptor Mol Microbiol 41 2001 439 450 11489129 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Pseudomonas encodes a soluble cytoplasmic heme-binding protein, PhuS, that is not a heme oxygenase.

    “In contrast to many other organisms, Pseudomonas encodes a soluble cytoplasmic heme-binding protein that is not a heme oxygenase.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [160] Lansky IB Lukat-Rodgers GS Block D Rodgers KR Ratliff M Wilks A The cytoplasmic heme-binding protein (PhuS) from the heme uptake system of Pseudomonas aeruginosa is an intracellular heme-trafficking protein to the delta-regioselective heme oxygenase J Biol Chem 281 2006 13652 13662 16533806 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    When heme is available, HasS instead binds HasR, and HasI is free to recruit RNA polymerase to activate transcription of hasAR, hasSI, phuSTUV, and phuR.

    “When heme is available, HasS instead binds HasR, and HasI is free to recruit RNA polymerase to activate the transcription of hasAR, hasSI, phuSTUV, and phuR [157].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [157] Smith AD Wilks A Differential contributions of the outer membrane receptors PhuR and HasR to heme acquisition in Pseudomonas aeruginosa J Biol Chem 290 2015 7756 7766 25616666 PMC4367277 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The present model suggests that Phu is the principal heme acquisition system but full heme utilization requires HasA/HasR.

    “The present model (Fig. 3) for these two heme uptake systems suggests that Phu is the principle heme acquisition system but full heme utilization requires HasA/HasR.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [157] Smith AD Wilks A Differential contributions of the outer membrane receptors PhuR and HasR to heme acquisition in Pseudomonas aeruginosa J Biol Chem 290 2015 7756 7766 25616666 PMC4367277 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The Phu system consists of a TonB-dependent PhuR that binds heme and transports it to the periplasm.

    “The Phu (Pseudomonas heme uptake) consists of a TonB-dependent PhuR which binds heme and transports it to the periplasm.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [154] Noinaj N Guillier M Barnard TJ Buchanan SK TonB-dependent transporters: regulation, structure, and function Annu Rev Microbiol 64 2010 43 60 20420522 PMC3108441 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Upon PhuR translocation of heme into the periplasm, the soluble periplasmic protein PhuT binds heme and brings it to PhuUV, an ABC transporter at the inner membrane.

    “Upon PhuR translocation of heme into the periplasm, the soluble periplasmic protein PhuT binds heme and brings it to PhuUV, an ABC transporter at the inner membrane.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [154] Noinaj N Guillier M Barnard TJ Buchanan SK TonB-dependent transporters: regulation, structure, and function Annu Rev Microbiol 64 2010 43 60 20420522 PMC3108441 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    HasA is a secreted hemophore that binds heme and transfers it to a second TonB-dependent transporter, HasR.

    “HasA is a secreted hemophore that binds heme and transfers it to a second TonB-dependent transporter, HasR.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [155] Letoffe S Nato F Goldberg ME Wandersman C Interactions of HasA, a bacterial haemophore, with haemoglobin and with its outer membrane receptor HasR Mol Microbiol 33 1999 546 555 10417645 source

      Not checked in the free run.

    • cites [156] Letoffe S Deniau C Wolff N Dassa E Delepelaire P Lecroisey A Haemophore-mediated bacterial haem transport: evidence for a common or overlapping site for haem-free and haem-loaded haemophore on its specific outer membrane receptor Mol Microbiol 41 2001 439 450 11489129 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    PhuR activity is representative of Gram-negative TonB-dependent outer-membrane receptors.

    “PhuR activity is representative of Gram-negative TonB-dependent outer-membrane receptors.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [154] Noinaj N Guillier M Barnard TJ Buchanan SK TonB-dependent transporters: regulation, structure, and function Annu Rev Microbiol 64 2010 43 60 20420522 PMC3108441 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Heme coordination in PhuS occurs primarily at His212 and induces a conformational change needed for HemO interaction.

    “Further in vitro characterization and structural analysis has led to a model whereby heme coordination occurs primarily at the His212 ligand and induces a conformational change required for interaction with HemO [162,163].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [162] Tripathi S O'Neill MJ Wilks A Poulos TL Crystal structure of the Pseudomonas aeruginosa cytoplasmic heme binding protein, Apo-PhuS J Inorg Biochem 128 2013 131 136 23973453 PMC3843485 source

      Not checked in the free run.

    • cites [163] O'Neill MJ Bhakta MN Fleming KG Wilks A Induced fit on heme binding to the Pseudomonas aeruginosa cytoplasmic protein (PhuS) drives interaction with heme oxygenase (HemO) Proc Natl Acad Sci USA 109 2012 5639 5644 22451925 PMC3326490 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    These β-barrel proteins bind substrates with high affinity and rely on proton motive force and TonB for transport across the outer membrane.

    “These β-barrel proteins bind substrates (often iron containing molecules) with high affinity, and rely on proton motive force and TonB for transport across the outer membrane [154].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [154] Noinaj N Guillier M Barnard TJ Buchanan SK TonB-dependent transporters: regulation, structure, and function Annu Rev Microbiol 64 2010 43 60 20420522 PMC3108441 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    HasA/HasR may be more relevant as a heme sensing system; under low heme conditions, the inner-membrane HasS binds the sigma factor inhibitor HasI.

    “HasA/HasR may be more relevant as a heme sensing system; under low heme conditions, the inner-membrane HasS binds the sigma factor inhibitor HasI.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [157] Smith AD Wilks A Differential contributions of the outer membrane receptors PhuR and HasR to heme acquisition in Pseudomonas aeruginosa J Biol Chem 290 2015 7756 7766 25616666 PMC4367277 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    HxuA binds Hx with high affinity and little distinction between apo- and holo-Hx.

    “demonstrates high-affinity binding specifically to Hx with little distinction between apo- and holo-Hx [172].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [172] Fournier C Smith A Delepelaire P Haem release from haemopexin by HxuA allows Haemophilus influenzae to escape host nutritional immunity Mol Microbiol 80 2011 133 148 21276097 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    HpuB binds Hb, apo-Hp, and Hp-Hb.

    “capable of binding Hb, apo-Hp, and Hp–Hb [190,191].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [190] Lewis LA Gray E Wang YP Roe BA Dyer DW Molecular characterization of hpuAB, the haemoglobin–hapto-globin-utilization operon of Neisseria meningitidis Mol Microbiol 23 1997 737 749 9157245 source

      Not checked in the free run.

    • cites [191] Lewis LA Dyer DW Identification of an iron-regulated outer membrane protein of Neisseria meningitidis involved in the utilization of hemoglobin complexed to haptoglobin J Bacteriol 177 1995 1299 1306 7868605 PMC176737 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    HxuC is a TonB-dependent transporter that binds heme after release from the Hx-heme-HxuA complex and imports it into the periplasm.

    “HxuC is a TonB-dependent transporter that binds heme after release from the Hx–heme–HxuA complex and imports it into the periplasm [173].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [173] Cope LD Love RP Guinn SE Gilep A Usanov S Estabrook RW Involvement of HxuC outer membrane protein in utilization of hemoglobin by Haemophilus influenzae Infect Immun 69 2001 2353 2363 11254593 PMC98165 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Heme is extracted from hemoproteins and imported intact in N. meningitidis.

    “Heme is extracted from these hemoproteins and is imported intact”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [194] Lewis LA Sung MH Gipson M Hartman K Dyer DW Transport of intact porphyrin by HpuAB, the hemoglobin– haptoglobin utilization system of Neisseria meningitidis J Bacteriol 180 1998 6043 6047 9811666 PMC107682 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    HmbR is subject to phase variation.

    “Like HpuAB, it is subject to phase variation [202].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [202] Richardson AR Stojiljkovic I HmbR, a hemoglobin-binding outer membrane protein of Neisseria meningitidis, undergoes phase variation J Bacteriol 181 1999 2067 2074 10094683 PMC93618 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    HmbR binds host Hb with species specificity, utilizing human Hb more than other species.

    “HmbR (Hb receptor) is an additional N. meningitidis heme uptake protein that binds host Hb with species specificity, exhibiting a greater utilization of human Hb”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [200] Stojiljkovic I Hwa V de Saint Martin L O'Gaora P Nassif X Heffron F The Neisseria meningitidis haemoglobin receptor: its role in iron utilization and virulence Mol Microbiol 15 1995 531 541 7783623 source

      Not checked in the free run.

    • cites [201] Stojiljkovic I Larson J Hwa V Anic S So M HmbR outer membrane receptors of pathogenic Neisseria spp.: iron-regulated, hemoglobin-binding proteins with a high level of primary structure conservation J Bacteriology 178 1996 4670 4678 PMC178238 8755899 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    HpuA is required for growth with Hb as sole iron source and for heme import.

    “HpuA is required for growth with Hb as a sole iron source and heme import [198].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [198] Rohde KH Gillaspy AF Hatfield MD Lewis LA Dyer DW Interactions of haemoglobin with the Neisseria meningitidis receptor HpuAB: the role of TonB and an intact proton motive force Mol Microbiol 43 2002 335 354 11985713 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    HpuA and HpuA homologs interact with Hb, and this interaction is required for HpuAB-mediated heme uptake.

    “they suggest that HpuA and HpuA homologs interact with Hb, and this interaction is required for HpuAB-mediate heme uptake.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [199] Wong CT Xu Y Gupta A Garnett JA Matthews SJ Hare SA Structural analysis of haemoglobin binding by HpuA from the Neisseriaceae family Nat Commun 6 2015 10172 26671256 PMC4703857 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Excess heme is toxic, and invading pathogens must contend with heme toxicity during infection.

    “Paradoxically, excess heme is toxic and thus during infection, invading pathogens must contend with heme toxicity as a component of pathogenesis.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [25] Everse J Hsia N The toxicities of native and modified hemoglobins Free Radic Biol Med 22 1997 1075 1099 9034247 source

      Not checked in the free run.

    • cites [219] Chou AC Fitch CD Mechanism of hemolysis induced by ferriprotoporphyrin IX J Clin Invest 68 1981 672 677 7276166 PMC370848 source

      Not checked in the free run.

    • cites [220] Schmitt TH Frezzatti WA Jr Schreier S Hemin-induced lipid membrane disorder and increased permeability: a molecular model for the mechanism of cell lysis Arch Biochem Biophys 307 1993 96 103 8239671 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    HmbR cannot bind the Hp-Hb complex and likely binds free Hb only.

    “is unable to bind the Hp-Hb complex and therefore likely binds free Hb only [200,201].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [200] Stojiljkovic I Hwa V de Saint Martin L O'Gaora P Nassif X Heffron F The Neisseria meningitidis haemoglobin receptor: its role in iron utilization and virulence Mol Microbiol 15 1995 531 541 7783623 source

      Not checked in the free run.

    • cites [201] Stojiljkovic I Larson J Hwa V Anic S So M HmbR outer membrane receptors of pathogenic Neisseria spp.: iron-regulated, hemoglobin-binding proteins with a high level of primary structure conservation J Bacteriology 178 1996 4670 4678 PMC178238 8755899 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Under heme stress, hrtAB and pefAB/RCD are highly expressed, and the Pef systems are required for resistance to heme toxicity.

    “In heme stress, hrtAB and pefAB/RCD are expressed at high levels, and the Pef systems are required for resistance to heme toxicity [223].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [223] Fernandez A Lechardeur D Derre-Bobillot A Couve E Gaudu P Gruss A Two coregulated efflux transporters modulate intracellular heme and protoporphyrin IX availability in Streptococcus agalactiae PLoS Pathog 6 2010 e1000860 20421944 PMC2858704 source

      Not checked in the free run.

  • May combine two claims. The quote only partly states this claim.

    Premisecitation

    Heme-mediated ROS is key to heme toxicity, and heme toxicity is primarily localized to the membrane.

    “this work also localized heme toxicity primarily to the membrane.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [228] Wakeman CA Hammer ND Stauff DL Attia AS Anzaldi LL Dikalov SI Menaquinone biosynthesis potentiates haem toxicity in Staphylococcus aureus Mol Microbiol 86 2012 1376 1392 23043465 PMC3524387 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Heme accumulation results in excess iron by two mechanisms, both likely active under aerobic conditions.

    “The accumulation of heme results in excess iron by one of two mechanisms, both of which are likely at play under aerobic conditions.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Superoxide production is a separate source of oxidative damage from ferrous iron-mediated ROS and is a major component of heme damage in S. aureus.

    “Superoxide production is a separate source of oxidative damage from ferrous iron-mediated ROS and is a major component of heme damage in S. aureus [228].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [228] Wakeman CA Hammer ND Stauff DL Attia AS Anzaldi LL Dikalov SI Menaquinone biosynthesis potentiates haem toxicity in Staphylococcus aureus Mol Microbiol 86 2012 1376 1392 23043465 PMC3524387 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Streptococcus agalactiae encodes an HrtAB orthologue and a dual efflux system PefAB and PefRCD.

    “Streptococcus agalactiae encodes an orthologue of HrtAB, as well as a dual efflux system PefAB and PefRCD [223].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [223] Fernandez A Lechardeur D Derre-Bobillot A Couve E Gaudu P Gruss A Two coregulated efflux transporters modulate intracellular heme and protoporphyrin IX availability in Streptococcus agalactiae PLoS Pathog 6 2010 e1000860 20421944 PMC2858704 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In B. anthracis, an HssRS orthologue controls HrtAB expression and cross-talks with a second TCS responding to envelope stress.

    “In B. anthracis, an HssRS orthologue controls the expression of HrtAB and cross-talks with a second TCS that responds to cellular envelope stresses”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [238] Mike LA Choby JE Brinkman PR Olive LQ Dutter BF Ivan SJ Two-component system cross-regulation integrates Bacillus anthracis response to heme and cell envelope stress PLoS Pathog 10 2014 e1004044 24675902 PMC3968170 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Non-iron protoporphyrins are toxic to bacteria and activate the cellular response to heme toxicity.

    “non-iron protoporphyrins are toxic to bacteria and activate the cellular response to heme toxicity [229–231].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [229] Wakeman CA Stauff DL Zhang Y Skaar EP Differential activation of Staphylococcus aureus heme detoxification machinery by heme analogues J Bacteriol 196 2014 1335 1342 24443529 PMC3993332 source

      Not checked in the free run.

    • cites [230] Stojiljkovic I Kumar V Srinivasan N Non-iron metalloporphyrins: potent antibacterial compounds that exploit haem/Hb uptake systems of pathogenic bacteria Mol Microbiol 31 1999 429 442 10027961 source

      Not checked in the free run.

    • cites [231] Nitzan Y Wexler HM Finegold SM Inactivation of anaerobic bacteria by various photosensitized porphyrins or by hemin Curr Microbiol 29 1994 125 131 7765091 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Additional efflux systems exist, suggesting that efflux is a well-conserved strategy.

    “Additional efflux systems exist, suggesting that this strategy is well conserved.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Heme damage is similar to other hydrophobic molecules and may disrupt the Gram-negative outer membrane.

    “suggesting that damage by heme is similar to other hydrophobic molecules and may disrupt the Gram-negative outer membrane [224,233].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [224] Rasmussen AW Alexander HL Perkins-Balding D Shafer WM Stojiljkovic I Resistance of Neisseria meningitidis to the toxic effects of heme iron and other hydrophobic agents requires expression of ght J Bacteriol 187 2005 5214 5223 16030215 PMC1196014 source

      Not checked in the free run.

    • cites [233] Putker F Grutsch A Tommassen J Bos MP Ght protein of Neisseria meningitidis is involved in the regulation of lipopoly-saccharide biosynthesis J Bacteriol 196 2014 780 789 24296673 PMC3911185 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Under excess heme in S. aureus, membrane proteins are highly oxidized and superoxide is formed by redox cycling of heme-iron through membrane menaquinone.

    “In conditions of excess heme toxicity, membrane proteins are highly oxidized and superoxide is formed by redox cycling of heme-iron through membrane menaquinone [228].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [228] Wakeman CA Hammer ND Stauff DL Attia AS Anzaldi LL Dikalov SI Menaquinone biosynthesis potentiates haem toxicity in Staphylococcus aureus Mol Microbiol 86 2012 1376 1392 23043465 PMC3524387 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Heme is lipophilic and partitions to bacterial membranes, demonstrated in S. aureus, likely damaging membrane proteins and lipids.

    “The lipophilic nature of heme suggests that it partitions to the membrane of bacteria, and this has been demonstrated in S. aureus, likely resulting in damage to membrane proteins and lipids [84].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [84] Skaar EP Humayun M Bae T DeBord KL Schneewind O Iron-source preference of Staphylococcus aureus infections Science 305 2004 1626 1628 15361626 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    S. aureus IsdB exhibits species specificity and more efficiently utilizes human Hb relative to mouse Hb.

    “the Hb-binding IsdB of S. aureus exhibits species specificity and more efficiently utilizes human Hb relative to mouse Hb [86].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [86] Pishchany G McCoy AL Torres VJ Krause JC Crowe JE Jr Fabry ME Specificity for human hemoglobin enhances Staphylococcus aureus infection Cell Host Microbe 8 2010 544 550 21147468 PMC3032424 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    Based on limited evidence, exogenous heme is preferred when available.

    “Based on limited evidence, exogenous heme is preferred when available”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    Additional properties like oxygenase activity (PhuS and ChuS) and DNA binding (ShuS) have been observed for heme sequestration proteins.

    “additional properties like oxygenase (PhuS and ChuS) and DNA binding (ShuS) have been observed.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    The M. tuberculosis heme uptake system comprises three unique proteins and is sufficient to rescue growth of a heme auxotroph.

    “the Mycobacterium tuberculosis heme uptake system, which comprises three unique proteins and is sufficient to rescue the growth of a heme auxotroph”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [214] Parish T Schaeffer M Roberts G Duncan K HemZ is essential for heme biosynthesis in Mycobacterium tuberculosis Tuberculosis (Edinb) 85 2005 197 204 15850757 source

      Not checked in the free run.

    • cites [215] Tullius MV Harmston CA Owens CP Chim N Morse RP McMath LM Discovery and characterization of a unique mycobacterial heme acquisition system Proc Natl Acad Sci USA 108 2011 5051 5056 21383189 PMC3064333 source

      Not checked in the free run.

    • cites [216] Owens CP Chim N Goulding CW Insights on how the Mycobacterium tuberculosis heme uptake pathway can be used as a drug target Future Med Chem 5 2013 1391 1403 23919550 PMC3838433 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Interpretationnone given

    Heme uptake, synthesis, and toxicity processes are well conserved and vital to bacterial pathogenesis.

    “As the heme uptake, synthesis, and toxicity processes are well conserved and vital to bacterial pathogenesis”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    S. aureus Isd proteins have been targeted for vaccine development with mixed success, and monoclonal antibodies against IsdB have been studied therapeutically.

    “S. aureus Isd proteins have been the target of vaccine development with mixed success and monoclonal antibodies against IsdB have been studied for therapeutic use [209–213].”
    Quote in the paperNot a substantial claim0 of 5 sources checked
    • cites [209] Fowler VG Jr Proctor RA Where does a Staphylococcus aureus vaccine stand? Clin Microbiol Infect 20 5 2014 66 75 24476315 PMC4067250 source

      Not checked in the free run.

    • cites [210] Kuklin NA Clark DJ Secore S Cook J Cope LD McNeely T A novel Staphylococcus aureus vaccine: iron surface determinant B induces rapid antibody responses in rhesus macaques and specific increased survival in a murine S. aureus sepsis model Infect Immun 74 2006 2215 2223 16552052 PMC1418914 source

      Not checked in the free run.

    • cites [211] McNeely TB Shah NA Fridman A Joshi A Hartzel JS Keshari RS Mortality among recipients of the Merck V710 Staphylococcus aureus vaccine after postoperative S. aureus infections: an analysis of possible contributing host factors Hum Vaccin Immunother 10 2014 3513 3516 25483690 PMC4514053 source

      Not checked in the free run.

    • cites [212] Ebert T Smith S Pancari G Clark D Hampton R Secore S A fully human monoclonal antibody to Staphylococcus aureus iron regulated surface determinant B (IsdB) with functional activity in vitro and in vivo Hum Antibodies 19 2010 113 128 21178283 source

      Not checked in the free run.

    • cites [213] Pancari G Fan H Smith S Joshi A Haimbach R Clark D Characterization of the mechanism of protection mediated by CS-D7, a monoclonal antibody to Staphylococcus aureus iron regulated surface determinant B (IsdB) Front Cell Infect Microbiol 2 2012 36 22919628 PMC3417506 source

      Not checked in the free run.

137 of 137

  • The paper relies on this without support.

    Murine infection models are predictive of human bacterial pathogenesis.

    “heme biosynthesis is vital to cause disease in murine models of infection”

  • The paper relies on this without support.

    Transposon-sequencing and signature-tagged mutagenesis recovery defects indicate a gene's importance during infection.

    “genes with marked mutations that are recovered at a lower frequency from the infected tissue relative to growth in vitro are considered important to infection”

  • The paper relies on this without support.

    Animal models of H. influenzae infection reflect human pathogenesis.

    “Several animal models have been used to demonstrate the role of heme uptake during H. influenzae infection.”

  • The paper relies on this without support.

    Animal models of N. meningitidis meningitis reflect human virulence.

    “HmbR is required for virulence in an infant rat model of meningitis [200].”

  • The paper relies on this without support.

    In vitro heme utilization by H. influenzae reflects its in vivo infection biology.

    “H. influenzae has evolved a variety of heme uptake systems important for growth in vitro using various host heme sources.”
5 of 5

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • If haemoglobin or haem is released from erythrocytes, it is rapidly bound by host haemoproteins, haptoglobin or haemopexin (HPX), further preventing Fe use by pathogens.

    “If haemoglobin or haem is released from erythrocytes, it is rapidly bound by host haemoproteins, haptoglobin or haemopexin (HPX), further preventing Fe use by patho­ gens 13 .”

    From Nutritional immunity: the battle for nutrient metals at the host–pathogen interface (2022) · cites this paper as [13]

  • Haem biosynthesis is exquisitely regulated, with haem negatively regulating the activity of the rate-limiting biosynthetic enzyme HemA.

    “In addition to Fur‐mediated iron sensing, haem biosynthesis is also exquisitely regulated, with haem negatively regulating the activity of the rate‐limiting biosynthetic enzyme HemA. 85 , 86”

    From The battle for iron in enteric infections (2020) · cites this paper as [86]

  • Gram-positive pathogens such as Staphylococcus aureus, Bacillus anthracis, and Corynebacterium diphtheriae rely on heme acquisition systems to establish infection.

    “Gram-positive pathogenic bacteria, such as Staphylococcus aureus, Bacillus anthracis and Corynebacterium diphtheriae also rely on heme acquisition systems to establish infection (78).”

    From Innate Nutritional Immunity (2018) · cites this paper as [78]

  • Heme acquisition is required for virulence in Staphylococcus aureus, Bacillus anthracis, and Streptococcus pyogenes.

    “Heme acquisition is required for virulence in Staphylococcus aureus, B. anthracis, and Streptococcus pyogenes (27).”

    From Transition Metals and Virulence in Bacteria (2016) · cites this paper as [27]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • The same Haemophilus protein has two spellings

    Minor

    Adjacent sentences name what appears to be the same heme-acquisition lipoprotein HpbA and HbpA, leaving its designation inconsistent.

1 of 1

Cites

1 retracted

Flagged first, then by citations

6 of the 258 references couldn’t be matched to a known paper.

Cited by

Sorted by citations

Related

Authors
Choby, J. E., & Skaar, E. P.
Affiliations
  • Vanderbilt University (US)
  • United States Department of Veterans Affairs (US)
Corresponding author
Skaar, Eric P.
ORCID
Venue
Journal of Molecular Biology
Publisher
Elsevier BV
Published
2016-08
Volume
428
Issue
17
Pages
3408-3428
ISSN
0022-2836 (ISSN-L)
DOI
10.1016/j.jmb.2016.03.018
PMC
PMC5125930
OpenAlex
W2306188934
Cited by
343
References
258
Citations by year
2026: 26 · 2025: 53 · 2024: 40 · 2023: 32 · 2022: 39 · 2021: 37 · 2020: 34 · 2019: 32 · 2018: 24 · 2017: 18 · 2016: 6
FWCI
18.32
Type
journal article
Language
en
Open access
Licence
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations
  • Journal of Molecular Biology (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
NIH (T32 GM065086, AI069233, AI073843)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Hemoglobin structure and function
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Bacterial Genetics and Biotechnology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Endocrinology › Escherichia coli research studies
Keywords
heme biosynthesis, heme acquisition, pathogenic bacteria, hemoglobin, heme detoxification, iron acquisition, heme proteins, host-pathogen interaction, pathogenesis, electron transport chain
MeSH terms
Bacteria, Heme, Metabolic Networks and Pathways, Host-Pathogen Interactions

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-07.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-07.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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