Biosynthesis of heme in mammals
Open accessAbstract
Most iron in mammalian systems is routed to mitochondria to serve as a substrate for ferrochelatase. Ferrochelatase inserts iron into protoporphyrin IX to form heme which is incorporated into hemoglobin and cytochromes, the dominant hemoproteins in mammals. Tissue-specific regulatory features characterize the heme biosynthetic pathway. In erythroid cells, regulation is mediated by erythroid-specific transcription factors and the availability of iron as Fe/S clusters. In non-erythroid cells the pathway is regulated by heme-mediated feedback inhibition. All of the enzymes in the heme biosynthetic pathway have been crystallized and the crystal structures have permitted detailed analyses of enzyme mechanisms. All of the genes encoding the heme biosynthetic enzymes have been cloned and mutations of these genes are responsible for a group of human disorders designated the porphyrias and for X-linked sideroblastic anemia. The biochemistry, structural biology and the mechanisms of tissue-specific regulation are presented in this review along with the key features of the porphyric disorders.
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PpIX is produced by aromatization of protoporphyrinogen IX by PPOX and has fluorescent and photosensitizing properties.
“Protoporphyrinogen IX crosses the mitochondrial inner membrane and is aromatized by protoporphyrinogen oxidase (PPOX) to produce PpIX, a porphyrin metabolite with fluorescent and photosensitizing properties.”
From 5-Aminolevulinic Acid as a Theranostic Agent for Tumor Fluorescence Imaging and Photodynamic Therapy (2023) · cites this paper as [8]
Section 1.3 states that protoporphyrinogen IX is oxidized by PPO to protoporphyrin IX (PpIX) and that the resulting porphyrin is fluorescent. The Introduction links porphyrin fluorescence to photosensitivity. The paper does not say that protoporphyrinogen IX crosses the inner mitochondrial membrane before this reaction; section 1.3 places PPO on the membrane’s outer surface. (LLM, conf=0.88)
Experimental — accuracy not yet measuredHeme biosynthesis ends with insertion of ferrous iron into PpIX by ferrochelatase to form heme.
“Heme biosynthesis ends in the mitochondrial matrix where ferrous iron (Fe2+) is inserted into the tetrapyrrole core of PpIX by ferrochelatase (FECH) to form heme [8].”
From 5-Aminolevulinic Acid as a Theranostic Agent for Tumor Fluorescence Imaging and Photodynamic Therapy (2023) · cites this paper as [8]
Heme biosynthesis in mammalian cells involves eight enzymes, four in the cytoplasm and four in the mitochondrion.
“Heme biosynthesis in mammalian cells is a finely tuned process that involves eight enzymes with four in the cytoplasm and four in the mitochondrion [8], as shown in Figure 1.”
From 5-Aminolevulinic Acid as a Theranostic Agent for Tumor Fluorescence Imaging and Photodynamic Therapy (2023) · cites this paper as [8]
ALA is metabolized in the heme biosynthetic pathway to produce protoporphyrin IX (PpIX), a fluorophore and photosensitizing agent.
“As a porphyrin precursor, ALA is metabolized in the heme biosynthetic pathway to produce protoporphyrin IX (PpIX), a fluorophore and photosensitizing agent.”
From 5-Aminolevulinic Acid as a Theranostic Agent for Tumor Fluorescence Imaging and Photodynamic Therapy (2023) · cites this paper as [8]
Conjugation of eight ALA molecules yields protoporphyrin IX (PpIX) and finally leads to formation of heme.
“Conjugation of eight ALA molecules yields protoporphyrin IX (PpIX) and finally leads to formation of heme.”
From Aminolevulinic Acid (ALA) as a Prodrug in Photodynamic Therapy of Cancer (2011) · cites this paper as [9]
Synthesis of ALA is the first and rate-limiting step in the biosynthesis of heme.
“The synthesis of ALA is the first and rate-limiting step in the biosynthesis of heme [9,10,11].”
From Aminolevulinic Acid (ALA) as a Prodrug in Photodynamic Therapy of Cancer (2011) · cites this paper as [9]
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Self-citation
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- Authors
- Ajioka, R. S., Phillips, J. D., & Kushner, J. P.
- Affiliations
- University of Utah (US)
- Corresponding author
- Kushner, James P.
- ORCID
- Phillips, John D.
- Venue
- Biochimica et Biophysica Acta (BBA) - Molecular Cell Research
- Publisher
- Elsevier BV
- Published
- 2006-07
- Volume
- 1763
- Issue
- 7
- Pages
- 723-736
- ISSN
- 0167-4889 (ISSN-L)
- OpenAlex
- W2143881989
- Cited by
- 493
- References
- 108
- Citations by year
- 2026: 25 · 2025: 17 · 2024: 18 · 2023: 21 · 2022: 28 · 2021: 39 · 2020: 36 · 2019: 24 · 2018: 29 · 2017: 34 · 2016: 32 · 2015: 31 · 2014: 25 · 2013: 20 · 2012: 18
- FWCI
- 1.40
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Biochimica et Biophysica Acta (BBA) - Molecular Cell Research (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5r01dk020503-32)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK-20503, DK 062106, R01-DK020503)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Porphyrin Metabolism and Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Hemoglobin structure and function
- Physical Sciences › Materials Science › Materials Chemistry › Porphyrin and Phthalocyanine Chemistry
- Keywords
- heme biosynthesis, ferrochelatase, protoporphyrin IX, erythroid cells, iron availability, iron-sulfur clusters, enzyme crystal structure, porphyria, X-linked sideroblastic anemia, tissue-specific gene regulation, heme proteins
- MeSH terms
- Animals, Ferrochelatase, Heme, Mammals, Models, Molecular, Protein Conformation, Crystallography, X-Ray
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.
Statistics and arithmetic are recomputed, not judged.
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