Abstract
Heme is an iron-containing tetrapyrrole that plays a critical role in regulating a variety of biological processes including oxygen and electron transport, gas sensing, signal transduction, biological clock, and microRNA processing. Most metazoan cells synthesize heme via a conserved pathway comprised of eight enzyme-catalyzed reactions. Heme can also be acquired from food or extracellular environment. Cellular heme homeostasis is maintained through the coordinated regulation of synthesis, transport, and degradation. This review presents the current knowledge of the synthesis and transport of heme in metazoans and highlights recent advances in the regulation of these pathways.
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Korolnek T, Hamza I. Like iron in the blood of the people: the requirement for heme trafficking in iron metabolism. Front Pharmacol, 2014, 5: 1–13
Severance S, Hamza I. Trafficking of heme and porphyrins in metazoa. Chem Rev, 2009, 109: 4596–4616
Haldar M, Kohyama M, So AY, Wumesh KC, Wu XD, Briseno CG, Satpathy AT, Kretzer NM, Arase H, Rajasekaran NS, Wang L, Egawa T, Igarashi K, Baltimore D, Murphy TL, Murphy KM. Heme-mediated SPI-C induction promotes monocyte differentiation into iron-recycling macrophages. Cell, 2014, 156: 1223–1234
Ogawa K, Sun J, Taketani S, Nakajima O, Nishitani C, Sassa S, Hayashi N, Yamamoto M, Shibahara S, Fujita H, Igarashi K. Heme mediates derepression of Maf recognition element through direct binding to transcription repressor Bach1. EMBO J, 2001, 20: 2835–2843
Suzuki H, Tashiro S, Hira S, Sun J, Yamazaki C, Zenke Y, Ikeda-Saito M, Yoshida M, Igarashi K. Heme regulates gene expression by triggering Crm1-dependent nuclear export of Bach1. EMBO J, 2004, 23: 2544–2553
Warnatz HJ, Schmidt D, Manke T, Piccini I, Sultan M, Borodina T, Balzereit D, Wruck W, Soldatov A, Vingron M, Lehrach H, Yaspo ML. The BTB and CNC homology 1 (BACH1) target genes are involved in the oxidative stress response and in control of the cell cycle. J Biol Chem, 2011, 286: 23521–23532
Kaasik K, Lee CC. Reciprocal regulation of haem biosynthesis and the circadian clock in mammals. Nature, 2004, 430: 467–471
Lukat-Rodgers GS, Correia C, Botuyan MV, Mer G, Rodgers KR. Heme-based sensing by the mammalian circadian protein clock. Inorg Chem, 2010, 49: 6349–6365
Raghuram S, Stayrook KR, Huang P, Rogers PM, Nosie AK, McClure DB, Burris LL, Khorasanizadeh S, Burris TP, Rastinejad F. Identification of heme as the ligand for the orphan nuclear receptors REV-ERBα and REV-ERBβ. Nat Struct Mol Biol, 2007, 14: 1207–1213
Yin L, Wu N, Curtin JC, Qatanani M, Szwergold NR, Reid RA, Waitt GM, Parks DJ, Pearce KH, Wisely GB, Lazar MA. REV-ERBα, a heme sensor that coordinates metabolic and circadian pathways. Science, 2007, 318: 1786–1789
Shen J, Sheng XP, Chang ZN, Wu Q, Wang S, Xuan ZL, Li D, Wu YL, Shang YJ, Kong XT, Yu L, Li L, Ruan KC, Hu HY, Huang Y, Hui LJ, Xie D, Wang FD, Hu RG. Iron metabolism regulates p53 signaling through direct heme-p53 interaction and modulation of p53 localization, stability, and function. Cell Rep, 2014, 7: 180–193
Faller M, Matsunaga M, Yin S, Loo JA, Guo F. Heme is involved in microrna processing. Nat Struct Mol Biol, 2007, 14: 23–29
Quick-Cleveland J, Jacob JP, Weitz SH, Shoffner G, Senturia R, Guo F. The DGCR8 RNA-binding heme domain recognizes primary micrornas by clamping the hairpin. Cell Rep, 2014, 7: 1994–2005
Weitz SH, Gong M, Barr I, Weiss S, Guo F. Processing of microRNA primary transcripts requires heme in mammalian cells. Proc Natl Acad Sci USA, 2014, 111: 1861–1866
Naito Y, Takagi T, Higashimura Y. Heme oxygenase-1 and anti- inflammatory M2 macrophages. Arch Biochem Biophys, 2014, 564: 83–88
Wegiel B, Nemeth Z, Correa-Costa M, Bulmer AC, Otterbein LE. Heme oxygenase-1: a metabolic nike. Antioxid Redox Signal, 2014, 20: 1709–1722
Andrews NC. Disorders of iron metabolism. N Engl J Med, 1999, 341: 1986–1995
Chen C, Paw BH. Cellular and mitochondrial iron homeostasis in vertebrates. Biochim Biophys Acta, 2012, 1823: 1459–1467
Ishikawa Y, Maeda M, Pasham M, Aguet F, Tacheva-Grigorova SK, Masuda T, Yi H, Lee SU, Xu J, Teruya-Feldstein J, Ericsson M, Mullally A, Heuser J, Kirchhausen T, Maeda T. Role of the clathrin adaptor PICALM in normal hematopoiesis and polycythemia vera pathophysiology. Haematologica, 2015, 100: 439–451
Scotland PB, Heath JL, Conway AE, Porter NB, Armstrong MB, Walker JA, Klebig ML, Lavau CP, Wechsler DS. The picalm protein plays a key role in iron homeostasis and cell proliferation. PLoS One, 2012, 7: e44252
Suzuki M, Tanaka H, Tanimura A, Tanabe K, Oe N, Rai S, Kon S, Fukumoto M, Takei K, Abe T, Matsumura I, Kanakura Y, Watanabe T. The clathrin assembly protein picalm is required for erythroid maturation and transferrin internalization in mice. PLoS One, 2012, 7: e31854
Chen C, Garcia-Santos D, Ishikawa Y, Seguin A, Li L, Fegan KH, Hildick-Smith GJ, Shah DI, Cooney JD, Chen W, King MJ, Yien YY, Schultz IJ, Anderson H, Dalton AJ, Freedman ML, Kingsley PD, Palis J, Hattangadi SM, Lodish HF, Ward DM, Kaplan J, Maeda T, Ponka P, Paw BH. Snx3 regulates recycling of the transferrin receptor and iron assimilation. Cell Metab, 2013, 17: 343–352
Lim JE, Jin O, Bennett C, Morgan K, Wang F, Trenor CC, Fleming MD, Andrews NC. A mutation in Sec15l1 causes anemia in hemoglobin deficit (hbd) mice. Nat Genet, 2005, 37: 1270–1273
Zhang AS, Sheftel AD, Ponka P. The anemia of “haemoglobin- deficit” (hbd/hbd) mice is caused by a defect in transferrin cycling. Exp Hematol, 2006, 34: 593–598
Ohgami RS, Campagna DR, Greer EL, Antiochos B, McDonald A, Chen J, Sharp JJ, Fujiwara Y, Barker JE, Fleming MD. Identification of a ferrireductase required for efficient transferrin-dependent iron uptake in erythroid cells. Nat Genet, 2005, 37: 1264–1269
Ohgami RS, Campagna DR, McDonald A, Fleming MD. The steap proteins are metalloreductases. Blood, 2006, 108: 1388–1394
Fleming MD, Romano MA, Su MA, Garrick LM, Garrick MD, Andrews NC. Nramp2 is mutated in the anemic Belgrade (b) rat: evidence of a role for Nramp2 in endosomal iron transport. Proc Natl Acad Sci USA, 1998, 95: 1148–1153
Dong XP, Cheng X, Mills E, Delling M, Wang F, Kurz T, Xu H. The type IV mucolipidosis-associated protein TRPML1 is an endolysosomal iron release channel. Nature, 2008, 455: 992–996
Cheng X, Zhang X, Gao Q, Ali Samie M, Azar M, Tsang WL, Dong L, Sahoo N, Li X, Zhuo Y, Garrity AG, Wang X, Ferrer M, Dowling J, Xu L, Han R, Xu H. The intracellular Ca2+ channel MCOLN1 is required for sarcolemma repair to prevent muscular dystrophy. Nat Med, 2014, 20: 1187–1192
Frey AG, Nandal A, Park JH, Smith PM, Yabe T, Ryu MS, Ghosh MC, Lee J, Rouault TA, Park MH, Philpott CC. Iron chaperones PCBP1 and PCBP2 mediate the metallation of the dinuclear iron enzyme deoxyhypusine hydroxylase. Proc Natl Acad Sci USA, 2014, 111: 8031–8036
Nandal A, Ruiz JC, Subramanian P, Ghimire-Rijal S, Sinnamon RA, Stemmler TL, Bruick RK, Philpott CC. Activation of the hif prolyl hydroxylase by the iron chaperones PCBP1 and PCBP2. Cell Metab, 2011, 14: 647–657
Shi H, Bencze KZ, Stemmler TL, Philpott CC. A cytosolic iron chaperone that delivers iron to ferritin. Science, 2008, 320: 1207–1210
Shaw GC, Cope JJ, Li L, Corson K, Hersey C, Ackermann GE, Gwynn B, Lambert AJ, Wingert RA, Traver D, Trede NS, Barut BA, Zhou Y, Minet E, Donovan A, Brownlie A, Balzan R, Weiss MJ, Peters LL, Kaplan J, Zon LI, Paw BH. Mitoferrin is essential for erythroid iron assimilation. Nature, 2006, 440: 96–100
Paradkar PN, Zumbrennen KB, Paw BH, Ward DM, Kaplan J. Regulation of mitochondrial iron import through differential turnover of mitoferrin 1 and mitoferrin 2. Mol Cell Biol, 2009, 29: 1007–1016
Labbe RF, Kurumada T, Onisawa J. The role of succinyl-coa synthetase in the control of heme biosynthesis. Biochim Biophys Acta, 1965, 111: 403–415
Onisawa J, Labbe RF. Terminal oxidation in the regulation of heme biosynthesis. Science, 1963, 140: 1326–1327
Locasale JW. Serine, glycine and one-carbon units: cancer metabolism in full circle. Nat Rev Cancer, 2013, 13: 572–583
Wang W, Wu Z, Dai Z, Yang Y, Wang J, Wu G. Glycine metabolism in animals and humans: implications for nutrition and health. Amino Acids, 2013, 45: 463–477
Anderson DD, Quintero CM, Stover PJ. Identification of a de novo thymidylate biosynthesis pathway in mammalian mitochondria. Proc Natl Acad Sci USA, 2011, 108: 15163–15168
di Salvo ML, Contestabile R, Paiardini A, Maras B. Glycine consumption and mitochondrial serine hydroxymethyltransferase in cancer cells: the heme connection. Med Hypotheses, 2013, 80: 633–636
Guastella J, Brecha N, Weigmann C, Lester HA, Davidson N. Cloning, expression, and localization of a rat brain high-affinity glycine transporter. Proc Natl Acad Sci USA, 1992, 89: 7189–7193
Harvey RJ, Yee BK. Glycine transporters as novel therapeutic targets in schizophrenia, alcohol dependence and pain. Nat Rev Drug Discov, 2013, 12: 866–885
Liu QR, Lopez-Corcuera B, Mandiyan S, Nelson H, Nelson N. Cloning and expression of a spinal cord- and brain-specific glycine transporter with novel structural features. J Biol Chem, 1993, 268: 22802–22808
An X, Schulz VP, Li J, Wu K, Liu J, Xue F, Hu J, Mohandas N, Gallagher PG. Global transcriptome analyses of human and murine terminal erythroid differentiation. Blood, 2014, 123: 3466–3477
Schranzhofer M, Bergeron R, dos Santos DG, Ponka P. Glycine transporter 1 plays a crucial role in hemoglobinization. Am J Hematol, 2013, 88: E32–E33
Guernsey DL, Jiang H, Campagna DR, Evans SC, Ferguson M, Kellogg MD, Lachance M, Matsuoka M, Nightingale M, Rideout A, Saint-Amant L, Schmidt PJ, Orr A, Bottomley SS, Fleming MD, Ludman M, Dyack S, Fernandez CV, Samuels ME. Mutations in mitochondrial carrier family gene SLC25A38 cause nonsyndromic autosomal recessive congenital sideroblastic anemia. Nat Genet, 2009, 41: 651–653
Liu G, Guo S, Kang H, Zhang F, Hu Y, Wang L, Li M, Ru Y, Camaschella C, Han B, Nie G. Mutation spectrum in chinese patients affected by congenital sideroblastic anemia and a search for a genotype- phenotype relationship. Haematologica, 2013, 98: e158–e160
Gotoh S, Nakamura T, Kataoka T, Taketani S. Egr-1 regulates the transcriptional repression of mouse δ-aminolevulinic acid synthase 1 by heme. Gene, 2011, 472: 28–36
Yoshino K, Munakata H, Kuge O, Ito A, Ogishima T. Haeme-regulated degradation of δ-aminolevulinate synthase 1 in rat liver mitochondria. J Biochem, 2007, 142: 453–458
Riddle RD, Yamamoto M, Engel JD. Expression of δ-aminolevulinate synthase in avian cells: separate genes encode erythroid-specific and nonspecific isozymes. Proc Natl Acad Sci USA, 1989, 86: 792–796
Dandekar T, Stripecke R, Gray NK, Goossen B, Constable A, Johansson HE, Hentze MW. Identification of a novel iron-responsive element in murine and human erythroid δ-aminolevulinic acid synthase mRNA. EMBO J, 1991, 10: 1903–1909
Hentze MW, Muckenthaler MU, Andrews NC. Balancing acts: molecular control of mammalian iron metabolism. Cell, 2004, 117: 285–297
Hofer T, Wenger RH, Kramer MF, Ferreira GC, Gassmann M. Hypoxic up-regulation of erythroid 5-aminolevulinate synthase. Blood, 2003, 101: 348–350
Zhang FL, Shen GM, Liu XL, Wang F, Zhao HL, Yu J, Zhang JW. Hypoxic induction of human erythroid-specific δ-aminolevulinate synthase mediated by hypoxia-inducible factor 1. Biochemistry, 2011, 50: 1194–1202
Liu YL, Ang SO, Weigent DA, Prchal JT, Bloomer JR. Regulation of ferrochelatase gene expression by hypoxia. Life Sci, 2004, 75: 2035–2043
Crooks DR, Ghosh MC, Haller RG, Tong WH, Rouault TA. Posttranslational stability of the heme biosynthetic enzyme ferrochelatase is dependent on iron availability and intact iron-sulfur cluster assembly machinery. Blood, 2010, 115: 860–869
Shah DI, Takahashi-Makise N, Cooney JD, Li L, Schultz IJ, Pierce EL, Narla A, Seguin A, Hattangadi SM, Medlock AE, Langer NB, Dailey TA, Hurst SN, Faccenda D, Wiwczar JM, Heggers SK, Vogin G, Chen W, Chen C, Campagna DR, Brugnara C, Zhou Y, Ebert BL, Danial NN, Fleming MD, Ward DM, Campanella M, Dailey HA, Kaplan J, Paw BH. Mitochondrial Atpif1 regulates haem synthesis in developing erythroblasts. Nature, 2012, 491: 608–612
Chen W, Dailey HA, Paw BH. Ferrochelatase forms an oligomeric complex with mitoferrin-1 and Abcb10 for erythroid heme biosynthesis. Blood, 2010, 116: 628–630
Yamamoto M, Arimura H, Fukushige T, Minami K, Nishizawa Y, Tanimoto A, Kanekura T, Nakagawa M, Akiyama S, Furukawa T. Abcb10 role in heme biosynthesis in vivo: Abcb10 knockout in mice causes anemia with protoporphyrin IX and iron accumulation. Mol Cell Biol, 2014, 34: 1077–1084
Bayeva M, Khechaduri A, Wu R, Burke MA, Wasserstrom JA, Singh N, Liesa M, Shirihai OS, Langer NB, Paw BH, Ardehali H. ATP-binding cassette B10 regulates early steps of heme synthesis. Circ Res, 2013, 113: 279–287
Chen W, Paradkar PN, Li L, Pierce EL, Langer NB, Takahashi-Makise N, Hyde BB, Shirihai OS, Ward DM, Kaplan J, Paw BH. Abcb10 physically interacts with mitoferrin-1 (Slc25a37) to enhance its stability and function in the erythroid mitochondria. Proc Natl Acad Sci USA, 2009, 106: 16263–16268
Rhee HW, Zou P, Udeshi ND, Martell JD, Mootha VK, Carr SA, Ting AY. Proteomic mapping of mitochondria in living cells via spatially restricted enzymatic tagging. Science, 2013, 339: 1328–1331
Krishnamurthy PC, Du G, Fukuda Y, Sun D, Sampath J, Mercer KE, Wang J, Sosa-Pineda B, Murti KG, Schuetz JD. Identification of a mammalian mitochondrial porphyrin transporter. Nature, 2006, 443: 586–589
Helias V, Saison C, Ballif BA, Peyrard T, Takahashi J, Takahashi H, Tanaka M, Deybach JC, Puy H, Le Gall M, Sureau C, Pham BN, Le Pennec PY, Tani Y, Cartron JP, Arnaud L. Abcb6 is dispensable for erythropoiesis and specifies the new blood group system langereis. Nat Genet, 2012, 44: 170–173
Ferreira GC, Andrew TL, Karr SW, Dailey HA. Organization of the terminal two enzymes of the heme biosynthetic pathway. Orientation of protoporphyrinogen oxidase and evidence for a membrane complex. J Biol Chem, 1988, 263: 3835–3839
Koch M, Breithaupt C, Kiefersauer R, Freigang J, Huber R, Messerschmidt A. Crystal structure of protoporphyrinogen ix oxidase: a key enzyme in haem and chlorophyll biosynthesis. EMBO J, 2004, 23: 1720–1728
Yien YY, Robledo RF, Schultz IJ, Takahashi-Makise N, Gwynn B, Bauer DE, Dass A, Yi G, Li L, Hildick-Smith GJ, Cooney JD, Pierce EL, Mohler K, Dailey TA, Miyata N, Kingsley PD, Garone C, Hattangadi SM, Huang H, Chen W, Keenan EM, Shah DI, Schlaeger TM, DiMauro S, Orkin SH, Cantor AB, Palis J, Koehler CM, Lodish HF, Kaplan J, Ward DM, Dailey HA, Phillips JD, Peters LL, Paw BH. TMEM14C is required for erythroid mitochondrial heme metabolism. J Clin Invest, 2014, 124: 4294–4304
Nilsson R, Schultz IJ, Pierce EL, Soltis KA, Naranuntarat A, Ward DM, Baughman JM, Paradkar PN, Kingsley PD, Culotta VC, Kaplan J, Palis J, Paw BH, Mootha VK. Discovery of genes essential for heme biosynthesis through large-scale gene expression analysis. Cell Metab, 2009, 10: 119–130
Shayeghi M, Latunde-Dada GO, Oakhill JS, Laftah AH, Takeuchi K, Halliday N, Khan Y, Warley A, McCann FE, Hider RC, Frazer DM, Anderson GJ, Vulpe CD, Simpson RJ, McKie AT. Identification of an intestinal heme transporter. Cell, 2005, 122: 789–801
Rajagopal A, Rao AU, Amigo J, Tian M, Upadhyay SK, Hall C, Uhm S, Mathew MK, Fleming MD, Paw BH, Krause M, Hamza I. Haem homeostasis is regulated by the conserved and concerted functions of HRG-1 proteins. Nature, 2008, 453: 1127–1131
Quigley JG, Yang ZT, Worthington MT, Phillips JD, Sabo KM, Sabath DE, Berg CL, Sassa S, Wood BL, Abkowitz JL. Identification of a human heme exporter that is essential for erythropoiesis. Cell, 2004, 118: 757–766
Keel SB, Doty RT, Yang Z, Quigley JG, Chen J, Knoblaugh S, Kingsley PD, de Domenico I, Vaughn MB, Kaplan J, Palis J, Abkowitz JL. A heme export protein is required for red blood cell differentiation and iron homeostasis. Science, 2008, 319: 825–828
Korolnek T, Zhang J, Beardsley S, Scheffer GL, Hamza I. Control of metazoan heme homeostasis by a conserved multidrug resistance protein. Cell Metab, 2014, 19: 1008–1019
Chiabrando D, Marro S, Mercurio S, Giorgi C, Petrillo S, Vinchi F, Fiorito V, Fagoonee S, Camporeale A, Turco E, Merlo GR, Silengo L, Altruda F, Pinton P, Tolosano E. The mitochondrial heme exporter FLVCR1b mediates erythroid differentiation. J Clin Invest, 2012, 122: 4569–4579
White C, Yuan X, Schmidt PJ, Bresciani E, Samuel TK, Campagna D, Hall C, Bishop K, Calicchio ML, Lapierre A, Ward DM, Liu P, Fleming MD, Hamza I. HRG1 is essential for heme transport from the phagolysosome of macrophages during erythrophagocytosis. Cell Metab, 2013, 17: 261–270
Chakravarti R, Aulak KS, Fox PL, Stuehr DJ. Gapdh regulates cellular heme insertion into inducible nitric oxide synthase. Proc Natl Acad Sci USA, 2010, 107: 18004–18009
Ghosh A, Stuehr DJ. Soluble guanylyl cyclase requires heat shock protein 90 for heme insertion during maturation of the no-active enzyme. Proc Natl Acad Sci USA, 2012, 109: 12998–13003
Hrkal Z, Vodrazka Z, Kalousek I. Transfer of heme from ferrihemoglobin and ferrihemoglobin isolated chains to hemopexin. Eur J Biochem, 1974, 43: 73–78
Hvidberg V, Maniecki MB, Jacobsen C, Hojrup P, Moller HJ, Moestrup SK. Identification of the receptor scavenging hemopexin- heme complexes. Blood, 2005, 106: 2572–2579
Hada H, Shiraki T, Watanabe-Matsui M, Igarashi K. Hemopexin-dependent heme uptake via endocytosis regulates the Bach1 transcription repressor and heme oxygenase gene activation. Biochim Biophys Acta, 2014, 1840: 2351–2360
Chen C, Samuel TK, Sinclair J, Dailey HA, Hamza I. An intercellular heme-trafficking protein delivers maternal heme to the embryo during development in C. Elegans. Cell, 2011, 145: 720–731
Qiu A, Jansen M, Sakaris A, Min SH, Chattopadhyay S, Tsai E, Sandoval C, Zhao R, Akabas MH, Goldman ID. Identification of an intestinal folate transporter and the molecular basis for hereditary folate malabsorption. Cell, 2006, 127: 917–928
Yuan X, Protchenko O, Philpott CC, Hamza I. Topologically conserved residues direct heme transport in HRG-1-related proteins. J Biol Chem, 2012, 287: 4914–4924
Huynh C, Yuan X, Miguel DC, Renberg RL, Protchenko O, Philpott CC, Hamza I, Andrews NW. Heme uptake by Leishmania amazonensis is mediated by the transmembrane protein LHR1. PLoS Pathog, 2012, 8: e1002795
Chen C, Samuel TK, Krause M, Dailey HA, Hamza I. Heme utilization in the caenorhabditis elegans hypodermal cells is facilitated by heme-responsive gene-2. J Biol Chem, 2012, 287: 9601–9612
Philip M, Funkhouser SA, Chiu EY, Phelps SR, Delrow JJ, Cox J, Fink PJ, Abkowitz JL. Heme exporter FLVCR is required for T cell development and peripheral survival. J Immunol, 2015, 194: 1677–1685
Vinchi F, Ingoglia G, Chiabrando D, Mercurio S, Turco E, Silengo L, Altruda F, Tolosano E. Heme exporter FLVCR1a regulates heme synthesis and degradation and controls activity of cytochromes P450. Gastroenterology, 2014, 146: 1325–1338
Fiorito V, Neri F, Pala V, Silengo L, Oliviero S, Altruda F, Tolosano E. Hypoxia controls Flvcr1 gene expression in Caco2 cells through HIF2α and ETS1. Biochim Biophys Acta, 2014, 1839: 259–264
Ghosh A, Stasch JP, Papapetropoulos A, Stuehr DJ. Nitric oxide and heat shock protein 90 activate soluble guanylate cyclase by driving rapid change in its subunit interactions and heme content. J Biol Chem, 2014, 289: 15259–15271
Yang Z, Philips JD, Doty RT, Giraudi P, Ostrow JD, Tiribelli C, Smith A, Abkowitz JL. Kinetics and specificity of feline leukemia virus subgroup C receptor (FLVCR) export function and its dependence on hemopexin. J Biol Chem, 2010, 285: 28874–28882
Shemin D, Rittenberg D. The utilization of glycine for the synthesis of a porphyrin. J Biol Chem, 1945, 159: 567–568
Wriston JC, 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, 1955, 215: 603–611
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Sun, F., Cheng, Y. & Chen, C. Regulation of heme biosynthesis and transport in metazoa. Sci. China Life Sci. 58, 757–764 (2015). https://doi.org/10.1007/s11427-015-4885-5
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DOI: https://doi.org/10.1007/s11427-015-4885-5