Tetrapyrroles pp 116-127 | Cite as

Regulation of Mammalian Heme Biosynthesis

  • Amy E. Medlock
  • Harry A. Dailey
Part of the Molecular Biology Intelligence Unit book series (MBIU)


Regulation of the heme biosynthetic pathway in mammals occurs via two distinct mechanisms. These mechanisms reflect the fact that while most cells need to closely regulate relatively low levels of intracellular heme, differentiating erythroid cells must produce massive amounts of heme during a short period to satisfy the needs of hemoglobinization. In erythroid precursor cells all pathway enzymes are induced via erythroid-specific promoter elements and the first enzyme, erythroid-specific 5-aminolevulinate synthase (ALAS-2) encoded by a gene on the X chromosome, is also subject to translational regulation due to the presence of an iron-responsive element located in the 5′ end of the mRNA. In nonerythroid cells a house-keeping regulatory scheme exists where most regulation appears to be via transcriptional regulation of a housekeeping 5-aminolevulinate synthase (ALAS-1) that is encoded on human chromosome 3. While the proteins of the mature forms of ALAS-1 and ALAS-2 are highly similar, the regulatory elements that control their expression are distinctly different and only ALAS-2 mRNA possesses an iron-regulatory element. Additional regulatory features exist throughout the pathway, but the major regulation appears to occur at the level of ALAS.


Erythroid Differentiation Heme Biosynthesis Iron Responsive Element Erythroid Precursor Cell Variegate Porphyria 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Lascelles J. Tetrapyrrole Biosynthesis and Its Regulation. New York: WA Benjamin, 1964.Google Scholar
  2. 2.
    Riddle RD, Yamamoto M, Engel JD. Expression of delta-aminolevulinate synthase in avian cells: Separate genes encode erythroid-specific and nonspecific isozymes. Proc Natl Acad Sci USA 1989; 86:792–796.CrossRefPubMedGoogle Scholar
  3. 3.
    O’Brian MR, Thony-Meyer L. Biochemistry, regulation and genomics of haem biosynthesis in prokaryotes. Adv Microb Physiol 2002; 46:257–318.CrossRefPubMedGoogle Scholar
  4. 4.
    Bishop DF, Henderson AS, Astrin KH. Human delta-aminolevulinate synthase: Assignment of the housekeeping gene to 3p21 and the erythroid-specific gene to the X chromosome. Genomics 1990; 7:207–214.CrossRefPubMedGoogle Scholar
  5. 5.
    Sutherland GR, Baker E, Callen DF et al. 5-Aminolevulinate synthase is at 3p21 and thus not the primary defect in X-linked sideroblastic anemia. Am J Hum Genet 1988; 43:331–335.PubMedGoogle Scholar
  6. 6.
    Cox TC, Bawden MJ, Abraham NG et al. Erythroid 5-aminolevulinate synthase is located on the X chromosome. Am J Hum Genet 1990; 46:107–111.PubMedGoogle Scholar
  7. 7.
    May BK, Bhasker CR, Bawden MJ et al. Molecular regulation of 5-aminolevulinate synthase. Diseases related to heme biosynthesis. Mol Biol Med 1990; 7:405–421.PubMedGoogle Scholar
  8. 8.
    May BK, Dogra SC, Sadlon TJ et al. Molecular regulation of heme biosynthesis in higher vertebrates. Prog Nucleic Acid Res Mol Biol 1995; 51:1–51.CrossRefPubMedGoogle Scholar
  9. 9.
    Conboy JG, Cox TC, Bottomley SS et al. Human erythroid 5-aminolevulinate synthase. Gene structure and species-specific differences in alternative RNA splicing. J Biol Chem 1992; 267:18753–18758.PubMedGoogle Scholar
  10. 10.
    Dandekar T, Stripecke R, Gray NK et al. Identification of a novel iron-responsive element in murine and human δ-aminolevulinic acid synthase mRNA. EMBO J 1991; 10:1903–1909.PubMedGoogle Scholar
  11. 11.
    Cox TC, Bawden MJ, Martin A et al. Human erythroid 5-aminolevulinate synthase: Promoter analysis and identification of an iron-responsive element in the mRNA. EMBO J 1991; 10:1891–1902.PubMedGoogle Scholar
  12. 12.
    Dierks P. Molecular biology of eukaryotic 5-aminolevulinate synthase. Biosynthesis of Hemes and Chlorophylls. New York: McGraw Hill: 1990:201–233.Google Scholar
  13. 13.
    Schoenhaut DS, Curtis PJ. Structure of a mouse erythroid 5-aminolevulinate synthase gene and mapping of erythroid-specific DNAse I hypersensitive sites. Nucleic Acids Res 1989; 17:7013–7028.CrossRefPubMedGoogle Scholar
  14. 14.
    Sadlon TJ, Dell’Oso T, Surinya KH et al. Regulation of erythroid 5-aminolevulinate synthase expression during erythropoiesis. Int J Biochem Cell Biol 1999; 31:1153–1167.CrossRefPubMedGoogle Scholar
  15. 15.
    Zoller H, Decristoforo C, Weiss G. Erythroid 5-aminolevulinate synthase, ferrochelatase and DMT1 expression in erythroid progeniters: Differential pathways for erythropoietin and iron-dependent regulation. Brit J Haematol 2002; 118:619–626.CrossRefGoogle Scholar
  16. 16.
    Fukuda Y, Fujita H, Garbaczewski L et al. Regulation of beta-globin mRNA accumulation by heme in dimethyl sulfoxide (DMSO)-sensitive and DMSO-resistant murine erythroleukemia cells. Blood 1994; 83:1662–1667.PubMedGoogle Scholar
  17. 17.
    Yin X, Dailey HA. Erythroid 5-aminolevulinate synthase is required for erythroid differentiation in mouse embryonic stem cells. Blood Cells Mol Dis 1998; 24:41–53.CrossRefPubMedGoogle Scholar
  18. 18.
    Harigae H, Suwabe N, Weinstock PH et al. Deficient heme and globin synthesis in embryonic stem cells lacking the erythroid-specific delta-aminolevulinate synthase gene. Blood 1998; 91:798–805.PubMedGoogle Scholar
  19. 19.
    Surinya KH, Cox TC, May BK. Transcriptional regulation of the human erythroid 5-aminolevulinate synthase gene. Identification of promoter elements and role of regulatory proteins. J Biol Chem 1997; 272:26585–26594.CrossRefPubMedGoogle Scholar
  20. 20.
    Surinya KH, Cox TC, May BK. Identification and characterization of a conserved erythroid-speciofic enhancer located in intron 8 of human 5-aminolevulinate synthase 2 gene. J Biol Chem 1998; 273:16798–16809.CrossRefPubMedGoogle Scholar
  21. 21.
    Ruiz de Mena I, Fernandez-Moreno MA, Bornstein B et al. Structure and regulated expression of the delta-aminolevulinate synthase gene from Drosophila melanogaster. J Biol Chem 1999; 274:37321–37328.CrossRefPubMedGoogle Scholar
  22. 22.
    Bhasker CR, Burgiel G, Neupert B et al. The putative iron-responsive element in the human erythroid 5-aminolevulinate synthase mRNA mediates translational control. J Biol Chem 1993; 268:12699–12705.PubMedGoogle Scholar
  23. 23.
    Melefors O, Goossen B, Johansson HE et al. Translational control of 5-aminolevulinate synthase mRNA by iron-responsive elements in erythroid cells. J Biol Chem 1993; 268:5974–5978.PubMedGoogle Scholar
  24. 24.
    Ponka P. Cell biology of heme. Am J Med Sci 1999; 318:241–256.CrossRefPubMedGoogle Scholar
  25. 25.
    Ades IZ, Harpe KG. Biogenesis of mitochondrial proteins: Identification of the mature and precursor forms of the subunit of δ-aminolevulinic acid synthase from embryonic chick liver. J Biol Chem 1981; 250:9329–9333.Google Scholar
  26. 26.
    Lathrop JT, Timko MP. Regulation by heme of mitochondrial protein transport through a conserved amino acid motif. Science 1993; 259:522–525.CrossRefPubMedGoogle Scholar
  27. 27.
    Andrew TL, Riley PG, Dailey HA. Regulation of heme biosynthesis in higher animals. In: Dailey HA, ed. Biosynthesis of Heme and Chlorophylls. New York: McGraw-Hill, 1990:163–233.Google Scholar
  28. 28.
    Jover R, Hoffmann K, Meyer UA. Induction of 5-aminolevulinate synthase by drugs is independent of increased apocytochrome P450 synthesis. Biochem Biophys Res Commun 1996; 226:152–157.CrossRefPubMedGoogle Scholar
  29. 29.
    Roberts AG, Elder GH. Alternative splicing and tissue-specific transcription of human and rodent ubiquitous 5-aminolevulinate synthase (ALAS1) genes. Biochim Biophys Acta 2001; 1518:95–105.PubMedGoogle Scholar
  30. 30.
    Li B, Holloszy JO, Semenkovich CF. Respiratory uncoupling induces delta-aminolevulinate synthase expression through a nuclear respiratory factor-1-dependent mechanism in HeLa cells. J Biol Chem 1999; 274:17534–17540.CrossRefPubMedGoogle Scholar
  31. 31.
    Lake-Bullock H, Dailey HA. Biphasic ordered induction of heme synthesis in differentiating murine erythroleukemia cells: Role of erythroid 5-aminolevulinate synthase. Mol Cell Biol 1993; 13:7122–7132.PubMedGoogle Scholar
  32. 32.
    Fujita H, Yamamoto M, Yamajami T et al. Erythroleukemia differentiation. Distinctive responses of the erythroid-specific and the nonspecific 5-aminolevulinate synthase mRNA. J Biol Chem 1991; 266:17494–17502.PubMedGoogle Scholar
  33. 33.
    Chretien S, Dubart A, Beaupain D et al. Alternative transcription and splicing of the human porphobilinogen deaminase gene result either in tissue-specific or in housekeeping expression. Proc Natl Acad Sci USA 1988; 85:6–10.CrossRefPubMedGoogle Scholar
  34. 34.
    Grandchamp B, De Verneuil H, Beaumont C et al. Tissue-specific expression of porphobilinogen deaminase. Two isoenzymes from a single gene. Eur J Biochem 1987; 162:105–110.CrossRefPubMedGoogle Scholar
  35. 35.
    Gubin AN, Miller JL. Human erythroid porphobilinogen deaminase exists in 2 splice variants. Blood 2001; 97:815–817.CrossRefPubMedGoogle Scholar
  36. 36.
    Beaumont C, Porcher C, Picat C et al. The mouse porphobilinogen deaminase gene. Structural organization, sequence, and transcriptional analysis. J Biol Chem 1989; 264:14829–14834.PubMedGoogle Scholar
  37. 37.
    Porcher C, Pitiot G, Plumb M et al. Characterization of hypersensitive sites, protein-binding motifs, and regulatory elements in both promoters of the mouse porphobilinogen deaminase gene. J Biol Chem 1991; 266:10562–10569.PubMedGoogle Scholar
  38. 38.
    Meissner P, Adams P, Kirsch R. Allosteric inhibition of human lymphoblast and purified porphobilinogen deaminase by protoporphyrinogen and coproporphyrinogen. A possible mechanism for the acute attack of variegate porphyria. J Clin Invest 1993; 91:1436–1444.CrossRefPubMedGoogle Scholar
  39. 39.
    Kaya AH, Plewinska M, Wong DM et al. Human delta-aminolevulinate dehydratase (ALAD) gene: Structure and alternative splicing of the erythroid and housekeeping mRNAs. Genomics 1994; 19:242–248.CrossRefPubMedGoogle Scholar
  40. 40.
    Bishop TR, Miller MW, Wang A et al. Multiple copies of the ALA-D gene are located at the Lv locus in Mus domesticus mice. Genomics 1998; 48:221–231.CrossRefPubMedGoogle Scholar
  41. 41.
    Aizencang G, Solis C, Bishop DF et al. Human uroporphyrinogen-III synthase: Genomic organization, alternative promoters, and erythroid-specific expression. Genomics 2000; 70:223–231.CrossRefPubMedGoogle Scholar
  42. 42.
    Aizencang GI, Bishop DF, Forrest D et al. Uroporphyrinogen III synthase. An alternative promoter controls erythroid-specific expression in the murine gene. J Biol Chem 2000; 275:2295–2304.CrossRefPubMedGoogle Scholar
  43. 43.
    Romana M, Dubart A, Beaupain D et al. Structure of the gene for human uroporphyrinogen decarboxylase. Nucleic Acids Res 1987; 15:7343–7356.CrossRefPubMedGoogle Scholar
  44. 44.
    Moore MR, McColl KEL, Rimington C et al. Disorders of Porphyrin Metabolism. New York: Plenum: 1987.Google Scholar
  45. 45.
    Conder L, Woodard SI, Dailey HA. Multiple mechanisms for the regulation of haem synthesis during erythroid cell differentiation. Possible role for coproporphyrinogen oxidase. Biochem J 1991; 275:321–326.PubMedGoogle Scholar
  46. 46.
    Woodard SI, Dailey HA. Multiple regulatory steps in erythroid heme biosynthesis. Arch Biochem Biophys 2000; 384:375–378.CrossRefPubMedGoogle Scholar
  47. 47.
    Taketani S, Furukawa T, Furuyama K. Expression of coproporphyrinogen oxidase and synthesis of hemoglobin in human erythroleukemia K562 cells. Eur J Biochem 2001; 268:1705–1711.CrossRefPubMedGoogle Scholar
  48. 48.
    Takahashi S, Taketani S, Akasaka JE et al. Differential regulation of coproporphyrinogen oxidase gene between erythroid and nonerythroid cells. Blood 1998; 92:3436–3444.PubMedGoogle Scholar
  49. 49.
    Delfau-Larue MH, Martasek P, Grandchamp B. Coproporphyrinogen oxidase: Gene organization and description of a mutation leading to exon 6 skipping. Hum Mol Genet 1994; 3:1325–1330.CrossRefPubMedGoogle Scholar
  50. 50.
    Roberts AG, Whatley SD, Daniels J et al. Partial characterization and assignment of the gene for protoporphyrinogen oxidase and variegate porphyria to human chromosome 1q23. Hum Mol Gen 1995; 4:2387–2390.CrossRefPubMedGoogle Scholar
  51. 51.
    Dailey TA, McManus JF, Dailey HA. Characterization of the mouse protoporphyrinogen oxidase gene. Cell Mol Biol 2002; 48:61–69.PubMedGoogle Scholar
  52. 52.
    Taketani S, Inazawa J, Abe T et al. The human protoporphyrinogen oxidase gene (PPOX): Organization and location to chromosome 1. Genomics 1995; 29:698–703.CrossRefPubMedGoogle Scholar
  53. 53.
    Taketani S, Inazawa J, Nakahashi Y et al. Structure of the human ferrochelatase gene. Exon/intron gene organization and location of the gene to chromosome 18. Eur J Biochem 1992; 205:217–222.CrossRefPubMedGoogle Scholar
  54. 54.
    Chan RY, Schulman HM, Ponka P. Expression of ferrochelatase mRNA in erythroid and nonerythroid cells. Biochem J 1993; 292:343–349.PubMedGoogle Scholar
  55. 55.
    Brenner DA, Frasier F. Cloning of murine ferrochelatase. Proc Natl Acad Sci USA 1991; 88:849–853.CrossRefPubMedGoogle Scholar
  56. 56.
    Tugores A, Magness ST, Brenner DA. A single promoter directs both housekeeping and erythroid preferential expression of the human ferrochelatase gene. J Biol Chem 1994; 269:30789–30797.PubMedGoogle Scholar
  57. 57.
    Magness ST, Tugores A, Diala ES et al. Analysis of the human ferrochelatase promoter in transgenic mice. Blood 1998; 92:320–328.PubMedGoogle Scholar
  58. 58.
    Magness ST, Tugores A, Brenner DA. Analysis of ferrochelatase expression during hematopoietic development of embryonic stem cells. Blood 2000; 95:3568–3577.PubMedGoogle Scholar
  59. 59.
    Asano H, Li XS, Stamatoyannopoulos G. FKLF-2: A novel Krüppel-like transcriptional factor that activates globin and other erythroid lineage genes. Blood 2000; 95:3578–3584.PubMedGoogle Scholar
  60. 60.
    Taketani S, Mohri T, Hioki K et al. Structure and regulation of the mouse ferrochelatase gene. Gene 1999; 227:117–124.CrossRefPubMedGoogle Scholar
  61. 61.
    Muppala V, Lin CS, Lee YH. The role of HNF-1 alpha in controlling hepatic catalyase activity. Mol Pharm 2000; 57:93–100.Google Scholar
  62. 62.
    Dailey HA, Dailey TA, Wu CK et al. Ferrochelatase at the millennium: Structures, mechanisms and [2Fe-2S] clusters. Cell Mol Life Sci 2000; 57:1909–1926.CrossRefPubMedGoogle Scholar
  63. 63.
    Taketani S, Adachi Y, Nakahashi Y. Regulation of the expression of human ferrochelatase by intracellular iron levels. Eur J Biochem 2000; 267:4685–4692.CrossRefPubMedGoogle Scholar

Copyright information

© Landes Bioscience and Springer Science+Business Media 2009

Authors and Affiliations

  1. 1.Biomedical and Health Sciences Institute, Paul D. Coverdell CenterUniversity of GeorgiaAthensUSA

Personalised recommendations