Journal of Bioenergetics and Biomembranes

, Volume 27, Issue 2, pp 151–159 | Cite as

5-Aminolevulinate synthase and the first step of heme biosynthesis

  • Gloria C. Ferreira
  • Jian Gong


5-Aminolevulinate synthase catalyzes the condensation of glycine and succinyl-CoA to yield 5-aminolevulinate. In animals, fungi, and some bacteria, 5-aminolevulinate synthase is the first enzyme of the heme biosynthetic pathway. Mutations on the human erythroid 5-aminolevulinate synthase, which is localized on the X-chromosome, have been associated with X-linked sideroblastic anemia. Recent biochemical and molecular biological developments provide important insights into the structure and function of this enzyme. In animals, two aminolevulinate synthase genes, one housekeeping and one erythroid-specific, have been identified. In addition, the isolation of 5-aminolevulinate synthase genomic and cDNA clones have permitted the development of expression systems, which have tremendously increased the yields of purified enzyme, facilitating structural and functional studies. A lysine residue has been identified as the residue involved in the Schiff base linkage of the pyridoxal 5′-phosphate cofactor, and the catalytic domain has been assigned to the C-terminus of the enzyme. A conserved glycine-rich motif, common to all aminolevulinate synthases, has been proposed to be at the pyridoxal 5′phosphate-binding site. A heme-regulatory motif, present in the presequences of 5-aminolevulinate synthase precursors, has been shown to mediate the inhibition of the mitochondrial import of the precursor proteins in the presence of heme. Finally, the regulatory mechanisms, exerted by an iron-responsive element binding protein, during the translation of erythroid 5-aminolevulinate synthase mRNA, are discussed in relation to heme biosynthesis.

Key words

Heme 5-aminolevulinate pyridoxal 5′-phosphate mitochondria heme metabolism 


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  1. Akhtar, M., and Jordan, P. M. (1968).Chem. Commun. 1691–1692.Google Scholar
  2. Bawden, M. J., Borthwick, I. A., Healy, H. M., Morris, C. P., May, B. K. and Elliott, W. H. (1987).Nucleic Acids Res. 15, 8563.PubMedGoogle Scholar
  3. Biel, S. W., Wright, M. S., and Biel, A. J. (1988).J. Bacteriol. 170, 4382–4384.PubMedGoogle Scholar
  4. Bishop, D. F. (1990).Nucleic Acids Res. 18, 7187–7188.PubMedGoogle Scholar
  5. Bishop, D. F., Kitchen, H., Wood, W. A. (1981).Arch. Biochem. Biophys. 206, 380–391.PubMedGoogle Scholar
  6. Bishop, D. F., Henderson, A. S., and Astrin, K. H. (1990).Genomics 7, 207–214.PubMedGoogle Scholar
  7. Borthwick, I. A., Srivastava, G., Brooker, J. D., May, B. K., and Elliott, W. K. (1983).Biochem. J. 129, 615–620.Google Scholar
  8. Borthwick, I. A., Srivastava, G., Hobbs, A. A., Pirola, B. A., Brooker, J. D., May, B. K., and Elliott, W. K. (1984).Eur. J. Biochem. 144, 95–99.PubMedGoogle Scholar
  9. Borthwick, I. A., Srivastava, G., Day, A. R., Pirola, B. A., Snoswell, M. A., May, B. K., and Elliott, W. H. (1985).Eur. J. Biochem. 150, 481–484.PubMedGoogle Scholar
  10. Borthwick, I. A., Srivastava, G., Pirola, B. A., May, B. K., and Elliott, W. K. (1986).Methods Enzymol. 123, 395–401.PubMedGoogle Scholar
  11. Bottomley, S. S., May, B. K., Cox, T. C., Cotter, P. D., and Bishop, D. (1995).J. Bioenerg. Biomembr., this issue.Google Scholar
  12. Bradshaw, R. E., Dixon, S. W., Raitt, D. C., and Pillar, T. M., (1993).Curr. Genet. 23, 501–507.PubMedGoogle Scholar
  13. Braidotti, G., Borthwick, I. A., and May, B. K. (1993).J. Biol. chem. 268, 1109–1117.PubMedGoogle Scholar
  14. Branden, C., and Tooze, J. (1991). InIntroduction to Protein Structure (Branden, C., and Tooze, J., eds.). Garland, New York, pp. 141–159.Google Scholar
  15. Conboy, J. G., Cox, T. C., Bottomley, S. S., Bawden, M. J., and May, B. K. (1992).J. Biol. Chem. 267, 18753–18758.PubMedGoogle Scholar
  16. Cotter, P., Baumann, M., and Bishop, D. F. (1992).Proc. Natl. Acad. Sci. USA 89, 4028–4032.PubMedGoogle Scholar
  17. Cox, T. C., Bawden, M. J., Abraham, N. G., Bottomley, S. S., May, B. K., Baker, E., Chen, L. Z., and Sutherland, G. R. (1990).Am. J. Hum. Genet. 46, 107–111.PubMedGoogle Scholar
  18. Cox, T. C. Bawden, M. J., Martin, A., and May, B. K. (1991).EMBO J. 10, 1891–1902.PubMedGoogle Scholar
  19. Cox, T. C., Bottomley, S. S., Wiley, J. S., Bawden, M. J., Matthews, C. S., and May, B. K. (1994).N. Eng. J. Med. 330, 675–679.Google Scholar
  20. Dandekar, T., Stripeck, R., Gray, N. K., Goossen, B., Constable, A., Johanson, H. E., and Hentze, M. W. (1991).EMBO J. 10, 1903–1909.PubMedGoogle Scholar
  21. Dierks, P. (1990). InBiosynthesis of Heme and Chlorophylls (Dailey, H. A., ed.), McGraw-Hill, New York, pp. 201–233.Google Scholar
  22. Drolet, M., and Sasarman, A. (1991).Mol. Gen. Genet. 226, 250–256.PubMedGoogle Scholar
  23. Dzelzalns, V., Foley, T., and Beale, S. I. (1982).Arch. Biochem. Biophys. 216, 196–203.PubMedGoogle Scholar
  24. Elliott, W. H., May, B. K., Bawden, M. J. and Hansen, A. J. (1989). InGene Expression: Regulation at the RNA and Protein Levels (Kay, J., Hallard, F. J., and Mayer, R. J., eds.). Biochemical Society Symposium 55, The Biochemical Society, London, pp. 13–27.Google Scholar
  25. Emery, V. C., and Akhtar, M. (1987). InEnzyme Mechanisms (Page, M. I., and Williams, A., eds.), The Royal Society of Chemistry, London, pp. 345–389.Google Scholar
  26. Fanica-Gaignier, M., and Clement-Metral, J. (1973).Eur. J. Biochem. 40, 19–24.PubMedGoogle Scholar
  27. Ferreira, G. C., and Dailey, H. A. (1993).J. Biol. Chem. 268, 584–590.PubMedGoogle Scholar
  28. Ferreira, G. C., Neame, P. J., and Dailey, H. A. (1993).Protein Sci. 2, 1959–1965.PubMedGoogle Scholar
  29. Fraser, P. J., and Curtis, P. J. (1987).Genes Dev. 1, 855–861.PubMedGoogle Scholar
  30. Fujita, H., Yamamoto, M., Yamagami, T., Hayashi, N., and Sassa, S. (1991).J. Biol. Chem. 266, 17494–17502.PubMedGoogle Scholar
  31. Gibson, K. D., Laver, W. G., and Neuberger, A. (1958).Biochem. J. 70, 71–81.PubMedGoogle Scholar
  32. Gong, J., and Ferreira, G. C. (1995).Biochemistry 34, 1678–1685.PubMedGoogle Scholar
  33. Gray, N. E., and Hentze, M. W. (1994).EMBO J. 13, 3882–3891.PubMedGoogle Scholar
  34. Haldi, M., and Guarente, L. (1989).J. Biol. Chem. 264, 17107–17112.PubMedGoogle Scholar
  35. Hayashi, N., Watanabe, N., and Kikuchi, G. (1983).Biochem. Biophys. Res. Commun. 115, 700–706.PubMedGoogle Scholar
  36. Hyde, C. C., Ahmed, S. A., Padlan, E. A., Miles, E. W., and Davies, D. R. (1988).J. Biol. Chem. 263, 17857–17871.PubMedGoogle Scholar
  37. Jordan, P. M. (1991). InBiosynthesis of Tetrapyrroles. (Jordan, P.M., ed.), Elsevier, Amsterdam, pp. 1–66.Google Scholar
  38. Jordan, P. M., and Laghai-Newton, A. (1986).Methods Enzymol. 123, 435–443.PubMedGoogle Scholar
  39. Kikuchi, G., Kumar, A., Talmage, P., and Shemin, D. (1958).J. Biol. Chem. 233, 1214–1219.PubMedGoogle Scholar
  40. Klausner, R. D., Rouault, T., and Harford, J. B. (1993).Cell 72, 19–28.PubMedGoogle Scholar
  41. Laghai, A., and Jordan, P. M. (1976).Biochem. Soc. Trans. 4, 52–53.PubMedGoogle Scholar
  42. Lathrop, J. T., and Timko, M. P. (1993).Science 259, 522–525.PubMedGoogle Scholar
  43. Leong, S. A., Williams, P. H., and Ditta, G. S. (1985).Nucleic Acids Res. 13, 5965–5976.PubMedGoogle Scholar
  44. Marceau, M., Mcfall, E., Lewis, S. D., and Shafer, J. A. (1988).J. Biol. Chem. 263 16926–16933.PubMedGoogle Scholar
  45. May, B. K., Borthwick, I. A., Srivastava, G., Pirola, B. A., and Elliott, W. H. (1986).Curr. Top. Cell. Regul. 28, 233–262.PubMedGoogle Scholar
  46. May, B. K., Bhasker, C. R., Bawden, M. J., and Cox, T. C. (1990).Mol. Biol. Med. 7, 405–421.PubMedGoogle Scholar
  47. McClung, C. R., Somerville, J. E., Guerinot, M. L., and Chelm, B. K. (1987).Gene 54, 133–139.PubMedGoogle Scholar
  48. Melefors, O., Goossen, B., Johansson, H. E., Stripecke, R., Gray, N. K., and Hentze, M. W. (1993).J. Biol. Chem. 268, 5974–5978.PubMedGoogle Scholar
  49. Munakata, H., Tamagami, T., Nagai, T., Yamamoto, M., and Hayashi, N. (1993).J. Biochem. 114, 103–111.PubMedGoogle Scholar
  50. Nakakuki, M., Yamauchi, K., Hayashi, N., and Kikuchi, G. (1980).J. Biol. Chem. 255, 1738–1745.PubMedGoogle Scholar
  51. Nandi, D. L. (1978a).J. Biol. Chem. 253, 8872–8877.PubMedGoogle Scholar
  52. Nandi, D. L. (1978b).Arch. Biochem. Biophys. 188, 266–271.PubMedGoogle Scholar
  53. Neidl, E. L., and Kaplan, S. (1993).J. Bacterial. 175, 2292–2303.Google Scholar
  54. Ohashi, A., and Kikuchi, G. (1979).J. Biochem. 85, 239–247.PubMedGoogle Scholar
  55. Page, M. D., and Ferguson, S. J. (1994).J. Bacteriol. 176, 5919–5928.PubMedGoogle Scholar
  56. Riddle, R. D., Yamamoto, M., and Engel, J. D. (1989).Proc. Natl. Acad. Sci. USA 86, 792–796.PubMedGoogle Scholar
  57. Rouault, T., Stout, C. D., Kaptain, S., Harford, J. B., and Klausner, R. D. (1992).Cell 64, 881–883.Google Scholar
  58. Samaniego, F., Chin, J., Iwai, K., Rouault, T. A., and Klausner, R. D. (1994).J. Biol. Chem. 269, 30904–30910.PubMedGoogle Scholar
  59. Schoenhaut, D. S., and Curtis, P. J. (1986).Gene 48, 55–63.PubMedGoogle Scholar
  60. Schoenhaut, D. S., and Curtis, P. J. (1989).Nucleic Acids Res. 17, 7013–7028.PubMedGoogle Scholar
  61. Scholnick, P. L., Hammaker, L. E., and Marver, H. S. (1972).J. Biol. Chem. 247, 4126–4131.PubMedGoogle Scholar
  62. Srivastava, G., Borthwick, I. A., Brooker, J. D., May, B. K., and Elliott, W. H. (1982).Biochim. Biophys. Acta 109, 305–312.Google Scholar
  63. Srivastava, G., Borthwick, I. A., Brooker, J. D., Wallace, J. C., May, B. K., and Elliott, W. H. (1983).Biochem. Biophys. Res. Commun. 117, 344–349.PubMedGoogle Scholar
  64. Srivastava, G., Borthwick, I. A., Maguire, D. J., Elferink, C. J., Bawden, M. J., Mercer, J. F. B., and May, B. K. (1988).J. Biol. Chem. 263, 5202–5209.Google Scholar
  65. Srivastava, G., Bawden, M. J., Anderson, A., and May, B. K. (1989).Biochim. Biophys. Acta 1007, 192–195.PubMedGoogle Scholar
  66. Srivastava, G., Hansen, A. J., Bawden, M. J., and May, B. K., (1990).Mol. Pharmacol. 38, 486–493.PubMedGoogle Scholar
  67. Swindells, M. B. (1993).Protein Sci. 2, 2146–2153.PubMedGoogle Scholar
  68. Tait, G. H. (1973).Biochem. J. 131, 389–403.PubMedGoogle Scholar
  69. Urban-Grimal, D., Ribes, V., and Labbe-Bois, R. (1984).Curr. Genet. 8, 327–331.Google Scholar
  70. Urban-Grimal, D., Volland, C., Garnier, T., Dehoux, P., and Labbe-Bois, R. (1986).Eur. J. Biochem. 156, 511–519.PubMedGoogle Scholar
  71. Volland, C., and Felix, F. (1984).Eur. J. Biochem. 142, 551–557.PubMedGoogle Scholar
  72. Volland, C., and Urban-Grimal, D. (1988).J. Biol. Chem. 263, 8294–8299.PubMedGoogle Scholar
  73. Wada, O., Sassa, S., Takaku, F., Yano, Y.. Zurata, G., Nakao, K. (1967).Biochim. Biophys. Acta 148, 585–587.PubMedGoogle Scholar
  74. Warnick, G. R., and Burnham, B. F. (1971).J. Biol. Chem. 246, 6880–6885.PubMedGoogle Scholar
  75. Watanabe, N., Hayashi, N., and Kikuchi, G. (1984).Arch. Biochem. Biophys. 232, 118–126.PubMedGoogle Scholar
  76. Weber, I. T., Johnson, L. N., Wilson, K. S., Yeates, D. G. R., Wild, D. L., and Jenkins, J. A. (1978).Nature (London) 274, 433–437.Google Scholar
  77. Whiting, M. J., and Granick, S. (1976).J. Biol. Chem. 251, 1340–1346.PubMedGoogle Scholar
  78. Wright, M. S., Eckert, J. J., Biel, S. W., and Biel, A. J. (1991).FEMS Microbiol. Lett. 78, 339–342.Google Scholar
  79. Yamamoto, M., Hayashi, N., and Kikuchi, G. (1983).Biochem. Biophys. Res. Commun. 115, 225–231.PubMedGoogle Scholar
  80. Yamamoto, M., Yew, N. S., Federspeil, M., Dodgson, J. B., Hayashi, N., and Engel, J. D. (1985).Proc. Natl. Acad. Sci. USA 82, 3702–3706.PubMedGoogle Scholar
  81. Yamamoto, M. K., Engel, J. D., and Hiraga, K. (1988).J. Biol. Chem. 263, 15973–15979.PubMedGoogle Scholar
  82. Yamauchi, K., Hayashi, N., and Kikuchi, G. (1980).J. Biol. Chem. 255, 1746–1751.PubMedGoogle Scholar
  83. Yomogida, K., Yamamoto, M., Yamagami, T., Fujita, H., and Hayashi, N. (1993).J. Biochem. 113, 364–371.PubMedGoogle Scholar
  84. Zaman, Z., Jordan, P. M., and Akhtar, M. (1973).Biochem. J. 135, 257–263.PubMedGoogle Scholar

Copyright information

© Plenum Publishing Corporation 1995

Authors and Affiliations

  • Gloria C. Ferreira
    • 1
    • 2
    • 3
  • Jian Gong
    • 1
    • 2
  1. 1.Department of Biochemistry and Molecular Biology, College of MedicineUniversity of South FloridaTampa
  2. 2.Institute for Biomolecular ScienceUniversity of South FloridaTampa
  3. 3.The H. Lee Moffitt Cancer Center and Research InstituteUniversity of South FloridaTampa

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