Heme Synthesis and Acquisition in Bacterial Pathogens

In the paper

“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.”

What the sources say

• Partly supported

  The Introduction (page not available) describes transport across the outer membrane into the periplasm before inner-membrane translocation. It does not identify PhuR, PhuT, or PhuUV, or describe PhuT binding heme and delivering it to PhuUV; searches for those names and the heme-transfer pathway found no supporting passage. (LLM, conf=0.76)

  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 sourceExperimental — accuracy not yet measured

In the paper

“Heme, a porphyrin ring complexed with iron, serves as a redox active moiety required for the function of many cellular proteins.”

What the sources say

• Not checked yetcites [1] Chen JJ London IM Hemin enhances the differentiation of mouse 3T3 cells to adipocytes Cell 26 1981 117 122 6799206 source
• Not checked yetcites [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 yetcites [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 yetcites [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

In the paper

“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].”

What the sources say

• Not checked yetcites [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 yetcites [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 yetcites [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 yetcites [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 yetcites [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 yetcites [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

In the paper

“both heme acquisition and synthesis are important for pathogenesis”

In the paper

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

What the sources say

• Not checked yetcites [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 yetcites [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

In the paper

“Thus, nearly all organisms must satisfy the requirement for heme through either synthesis or acquisition.”

In the paper

“Heme is also an important molecule involved in diverse cellular processes including signaling, gas sensing, microRNA processing, and cellular differentiation [1–4].”

What the sources say

• Not checked yetcites [1] Chen JJ London IM Hemin enhances the differentiation of mouse 3T3 cells to adipocytes Cell 26 1981 117 122 6799206 source
• Not checked yetcites [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 yetcites [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 yetcites [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

In the paper

“The tetrapyrrole cofactor heme is important for the cellular processes of most organisms and essential to many lifeforms across domains of life.”

What the sources say

• Not checked yetcites [1] Chen JJ London IM Hemin enhances the differentiation of mouse 3T3 cells to adipocytes Cell 26 1981 117 122 6799206 source
• Not checked yetcites [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 yetcites [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 yetcites [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

In the paper

“Like heme, iron is nearly universally required for life, and only a few exceptions have been identified [5,6].”

What the sources say

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

In the paper

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

What the sources say

• Not checked yetcites [15] Cassat JE Skaar EP Iron in infection and immunity Cell Host Microbe 13 2013 509 519 23684303 PMC3676888 source

In the paper

“bacterial pathogens have developed exquisite tactics to overcome iron limitation and elaborate high-affinity iron receptors and chelators”

What the sources say

• Not checked yetcites [15] Cassat JE Skaar EP Iron in infection and immunity Cell Host Microbe 13 2013 509 519 23684303 PMC3676888 source

In the paper

“In serum, heme is immediately bound by the highly abundant albumin (kd ≈ 10 nM) then transferred to hemopexin (kd < 1 pM) [30].”

What the sources say

• Not checked yetcites [30] Tolosano E Altruda F Hemopexin: structure, function, and regulation DNA Cell Biol 21 2002 297 306 12042069 source

In the paper

“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].”

What the sources say

• Not checked yetcites [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 yetcites [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 yetcites [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

In the paper

“The heme is delivered to cells expressing the hemopexin receptor; these cells then degrade the heme using heme oxygenases [30].”

What the sources say

• Not checked yetcites [30] Tolosano E Altruda F Hemopexin: structure, function, and regulation DNA Cell Biol 21 2002 297 306 12042069 source

In the paper

“A series of enzymes produces protoporphyrin IX from ALA and iron is inserted, forming protoheme IX.”

What the sources say

• Not checked yetcites [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 yetcites [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 yetcites [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

In the paper

“Hb contains about two-thirds of the body's iron, and a single erythrocyte contains more than 280 million molecules of Hb [15,24].”

What the sources say

• Not checked yetcites [15] Cassat JE Skaar EP Iron in infection and immunity Cell Host Microbe 13 2013 509 519 23684303 PMC3676888 source
• Not checked yetcites [24] Bridges KR Seligman PA Disorders of Iron Metabolism J.B Lippincott Company New York 1995

In the paper

“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”

What the sources say

• Not checked yetcites [15] Cassat JE Skaar EP Iron in infection and immunity Cell Host Microbe 13 2013 509 519 23684303 PMC3676888 source
• Not checked yetcites [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 yetcites [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 yetcites [18] Juttukonda LJ Skaar EP Manganese homeostasis and utilization in pathogenic bacteria Mol Microbiol 97 2015 216 228 25898914 PMC4631260 source

In the paper

“Hemoproteins involved in tissue oxygen homeostasis include myoglobin and neuroglobin.”

What the sources say

• Not checked yetcites [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 yetcites [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

In the paper

“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].”

What the sources say

• Not checked yetcites [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 yetcites [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

In the paper

“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].”

What the sources say

• Not checked yetcites [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

In the paper

“Therefore, organisms have evolved elaborate strategies to acquire, store, and regulate intracellular iron for heme-dependent and other iron-dependent enzymes.”

In the paper

“The limited access of pathogens to metals serves as an antimicrobial strategy and limits bacterial replication.”

What the sources say

• Not checked yetcites [15] Cassat JE Skaar EP Iron in infection and immunity Cell Host Microbe 13 2013 509 519 23684303 PMC3676888 source
• Not checked yetcites [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 yetcites [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 yetcites [18] Juttukonda LJ Skaar EP Manganese homeostasis and utilization in pathogenic bacteria Mol Microbiol 97 2015 216 228 25898914 PMC4631260 source

In the paper

“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].”

What the sources say

• Not checked yetcites [13] Weinberg ED Iron and susceptibility to infectious disease Science 184 1974 952 956 4596821 source
• Not checked yetcites [14] Weinberg ED Nutritional immunity: host's attempt to withold iron from microbial invaders JAMA 231 1975 39 41 1243565 source

In the paper

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

What the sources say

• Not checked yetcites [15] Cassat JE Skaar EP Iron in infection and immunity Cell Host Microbe 13 2013 509 519 23684303 PMC3676888 source
• Not checked yetcites [24] Bridges KR Seligman PA Disorders of Iron Metabolism J.B Lippincott Company New York 1995

In the paper

“Heme is then bound by hemoproteins to serve a variety of intracellular and extracellular tasks.”

What the sources say

• Not checked yetcites [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 yetcites [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

In the paper

“To prevent excess heme toxicity, eukaryotic heme synthesis is highly regulated and heme homeostasis and sequestration are well orchestrated.”

What the sources say

• Not checked yetcites [25] Everse J Hsia N The toxicities of native and modified hemoglobins Free Radic Biol Med 22 1997 1075 1099 9034247 source
• Not checked yetcites [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

In the paper

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

What the sources say

• Not checked yetcites [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 yetcites [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

In the paper

“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].”

What the sources say

• Not checked yetcites [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 yetcites [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

In the paper

“HemG, in Gammaproteobacteria and some Alphaproteobactera and Deltaproteobacteria, uses the respiratory chain as its electron acceptor and is not dependent on oxygen [48].”

What the sources say

• Not checked yetcites [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

In the paper

“The addition of heme to cell extracts of E. coli reduces total HemA activity, without inhibiting the activity of the purified enzyme [58,59].”

What the sources say

• Not checked yetcites [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 yetcites [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

In the paper

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

What the sources say

• Not checked yetcites [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

In the paper

“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].”

What the sources say

• Not checked yetcites [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 yetcites [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

In the paper

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

In the paper

“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].”

What the sources say

• Not checked yetcites [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

In the paper

“Uroporphyrinogen III can be utilized for the synthesis of several tetrapyrrole-based cofactors.”

What the sources say

• Not checked yetcites [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 yetcites [43] Leeper FJ The biosynthesis of porphyrins, chlorophylls, and vitamin B12 Nat Prod Rep 4 1987 441 469 3325863 source

In the paper

“Uroporphyrinogen III decarboxylase (HemE) decarboxylates the four acetate side chains to methyl groups, producing coproporphyrinogen III, the next step in heme synthesis [42].”

What the sources say

• Not checked yetcites [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

In the paper

“HemJ is poorly characterized but represents the most common protoporphyrinogen oxidase among Alphaproteobactera and Deltaproteobacteria [49].”

What the sources say

• Not checked yetcites [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

In the paper

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

In the paper

“The Ahb enzymes of some archaea and sulfur-reducing bacteria can convert siroheme (produced from uroporphyrinogen) to heme [44,45].”

What the sources say

• Not checked yetcites [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 yetcites [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

In the paper

“Additionally, uroporphyrinogen III can be shunted from heme synthesis and converted to precorrin-2 to synthesize vitamin B12, coenzyme F430, and siroheme [43].”

What the sources say

• Not checked yetcites [43] Leeper FJ The biosynthesis of porphyrins, chlorophylls, and vitamin B12 Nat Prod Rep 4 1987 441 469 3325863 source

In the paper

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

What the sources say

• Not checked yetcites [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 yetcites [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

In the paper

“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].”

What the sources say

• Not checked yetcites [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

In the paper

“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].”

What the sources say

• Not checked yetcites [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 yetcites [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

In the paper

“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].”

What the sources say

• Not checked yetcites [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 yetcites [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

In the paper

“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].”

What the sources say

• Not checked yetcites [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 yetcites [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

In the paper

“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].”

What the sources say

• Not checked yetcites [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

In the paper

“In B. subtilis, hemEHY is induced anaerobically and hemAXCBL is induced by peroxide through de-repression of PerR [38,68].”

What the sources say

• Not checked yetcites [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 yetcites [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

In the paper

“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.”

In the paper

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

What the sources say

• Not checked yetcites [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 yetcites [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

In the paper

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

In the paper

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

In the paper

“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].”

What the sources say

• Not checked yetcites [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 yetcites [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 yetcites [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

In the paper

“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”

In the paper

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

What the sources say

• Not checked yetcites [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

In the paper

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

In the paper

“However, the contribution of heme synthesis to the pathogenesis of bacterial pathogens is largely understudied.”

In the paper

“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]”

What the sources say

• Not checked yetcites [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 yetcites [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 yetcites [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 yetcites [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

In the paper

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

What the sources say

• Not checked yetcites [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

In the paper

“Inactivation of hemA, which renders S. aureus heme deficient, causes the small-colony variant (SCV) phenotype [87].”

What the sources say

• Not checked yetcites [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

In the paper

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

In the paper

“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].”

What the sources say

• Not checked yetcites [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 yetcites [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 yetcites [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

In the paper

“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].”

What the sources say

• Not checked yetcites [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 yetcites [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

In the paper

“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].”

What the sources say

• Not checked yetcites [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 yetcites [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 yetcites [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

In the paper

“Similarly, IsdHN1 and N2 bind Hb and Hp, and IsdH-N3 extracts the heme.”

What the sources say

• Not checked yetcites [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

In the paper

“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].”

What the sources say

• Not checked yetcites [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 yetcites [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 yetcites [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

In the paper

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

What the sources say

• Not checked yetcites [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

In the paper

“IsdG and IsdI are required for growth using heme as a sole iron source and are expressed during infection [115,120].”

What the sources say

• Not checked yetcites [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 yetcites [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

In the paper

“IsdA, which is partially surface exposed, contains a single heme-binding NEAT domain [102].”

What the sources say

• Not checked yetcites [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

In the paper

“The current model (Fig. 2), supported by strong structural evidence, suggests that IsdB-N1 binds Hb, and IsdB-N2 extracts heme [111].”

What the sources say

• Not checked yetcites [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

In the paper

“The NEAT domains are 120–125 aa domains that constitute a conserved eight-stranded β-sandwich fold [104,105].”

What the sources say

• Not checked yetcites [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 yetcites [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

In the paper

“Exogenous heme accumulates in the membrane and is also capable of complementing the growth of heme-deficient mutants [84].”

What the sources say

• Not checked yetcites [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

In the paper

“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].”

What the sources say

• Not checked yetcites [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

In the paper

“The heme is then transferred either directly to IsdC or shuttled via IsdA to IsdC.”

What the sources say

• Not checked yetcites [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

In the paper

“IsdH contains three NEAT domains, N1 and N2 bind both Hb and Hp, andN3bindsheme [109,110].”

What the sources say

• Not checked yetcites [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 yetcites [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

In the paper

“A guinea pig infection model demonstrated that ΔisdCX1X2 was as virulent as wild type, yet these proteins are expressed during infection [134].”

What the sources say

• Not checked yetcites [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

In the paper

“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].”

What the sources say

• Not checked yetcites [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

In the paper

“B. anthracis also encodes other NEAT contain proteins; Hal contains a single NEAT domain and leucine-rich repeats, which extract heme from Hb [130].”

What the sources say

• Not checked yetcites [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

In the paper

“These are the first described Gram-positive hemophores and bind heme, Hb, and methemoglobin [125– 129].”

What the sources say

• Not checked yetcites [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 yetcites [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 yetcites [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 yetcites [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 yetcites [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

In the paper

“The current proposed model (Fig. 2) is that IsdX1 is secreted, binds heme, and transfers heme to wall-anchored IsdC.”

What the sources say

• Not checked yetcites [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

In the paper

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

What the sources say

• Not checked yetcites [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

In the paper

“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.”

In the paper

“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.”

In the paper

“A second, recently described NEAT protein is BslK, which is non-covalently attached to the cell wall and transfers heme to IsdC [132].”

What the sources say

• Not checked yetcites [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

In the paper

“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].”

What the sources say

• Not checked yetcites [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 yetcites [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

In the paper

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

What the sources say

• Not checked yetcites [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

In the paper

“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].”

What the sources say

• Not checked yetcites [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 yetcites [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 yetcites [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 yetcites [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 yetcites [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 yetcites [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 yetcites [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

In the paper

“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].”

What the sources say

• Not checked yetcites [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

In the paper

“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].”

What the sources say

• Not checked yetcites [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