Cell Biochemistry and Biophysics

, Volume 46, Issue 1, pp 43–64 | Cite as

The α-aminoadipate pathway for lysine biosynthesis in fungi

  • Hengyu Xu
  • Babak Andi
  • Jinghua Qian
  • Ann H. WestEmail author
  • Paul F. CookEmail author


This review provides a description of the biochemistry and enzymology of the α-aminoadipate pathway for lysine biosynthesis in fungi. The α-aminoadipate pathway is unique to fungi and is thus a potential target for the rational design of antifungal drugs. The present state of knowledge of the mechanisms of the seven enzymes in the pathway is presented, as well as detailed information with respect to structures and mechanisms of homocitrate synthase, saccharopine reductase, and saccharopine dehydrogenase.

Index Entries

α-Aminoadipate pathway lysine biosynthesis in fungi homocitrate synthase Claisen condensation α-aminoadipate reductase saccharopine reductase saccharopine dehydrogenase pyridine nucleotide-linked amino acid oxidoreductase antifungal drugs 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Zabriskie, T. M. and Jackson, M. D. (2000) Lysine biosynthesis and metabolism in fungi. Nat. Prod. Rep. 17, 85–97.PubMedGoogle Scholar
  2. 2.
    Umbargar, H. E. (1978) Amino acid biosynthesis and its regulation. Annu. Rev. Biochem. 47, 533–606.Google Scholar
  3. 3.
    Bhattacharjee, J. K. (1985) α-Aminoadipate pathway for the biosynthesis of lysine in lower eukaryotes. Crit. Rev. Microbiol. 12, 131–151.PubMedGoogle Scholar
  4. 4.
    Bhattacharjee, J. K. (1992) Evolution of α-aminoadipate pathway for the synthesis of lysine in fungi, in Handbook of Evolution of Metabolic Function (Mortlock, R. P., ed.), CRC Press, Boca Raton, FL, pp. 47–80.Google Scholar
  5. 5.
    Vogel, H. J. (1960) Two modes lysine synthesis among lower fungi: evolutionary significance. Biochim. Biophys. Acta 41, 172–174.Google Scholar
  6. 6.
    Berges, D. A., DeWolf, W. E., Jr., Dunn, G. L., et al. (1986) Peptides of 2-aminopimelic acid: antibacterial agents that inhibit diaminopimelic acid biosynthesis. J. Med. Chem. 29, 89–95.PubMedGoogle Scholar
  7. 7.
    Bhattacharjee, J. K. and Strassman, M. (1967) Accumulation of tricarboxylic acids related to lysine biosynthesis in a yeast mutant. J. Biol. Chem. 242, 2542–2546.PubMedGoogle Scholar
  8. 8.
    Gaillardin, C. M., Ribert, A. M. and Heslot, H. (1982) Wild type and mutant forms of homoisocitric dehydrogenase in the yeast Saccharomycopsis lipolytica. Eur. J. Biochem. 128, 489–494.PubMedGoogle Scholar
  9. 9.
    Ye, Z. H. and Bhattacharjee, J. K. (1988) Lysine biosynthesis pathway and biochemical blocks of lysine auxotrophs of Schizosaccharomyces pombe. J. Bacteriol. 170, 5968–5970.PubMedGoogle Scholar
  10. 10.
    Glass, J. and Bhattacharjee, J. K. (1971) Biosynthesis of lysine in R. glutinis: accumulation of homocitric, homoaconitic, and homoisocitric acids in a leaky mutant. Genetics 67, 365–376.PubMedGoogle Scholar
  11. 11.
    Kunze, G., Bode, R., Schmidt, H., Samsonova, I. A., and Birnbaum D. (1987) Identification of a lys2 mutant of C. maltosa by means of transformation. Curr. Genet. 11, 385–391.PubMedGoogle Scholar
  12. 12.
    Broquist, H. P. (1971) Lysine biosynthesis (yeast). Methods Enzymol. 17, 112–129.Google Scholar
  13. 13.
    Jaklitsch, W. M. and Kubicek, C. P. (1990) Homocitrate synthase from Penicillium chrysogenum. Localization, purification of the cytosolic isoenzyme, and sensitivity to lysine. Biochem. J. 269, 247–253.PubMedGoogle Scholar
  14. 14.
    Garrad, R. C. and Bhattacharjee, J. K. (1992) Lysine biosynthesis in selected pathogenic fungi: characterization of lysine auxotrophs and the cloned LYS1 gene of Candida albicans. J. Bacteriol. 174, 7379–7384.PubMedGoogle Scholar
  15. 15.
    Andi, B., West, A. H., and Cook, P. F. (2004) Stabilization and characterization of histidine-tagged homocitrate synthase from Saccharomyces cerevisiae. Arch. Biochem. Biophys. 421, 243–254.PubMedGoogle Scholar
  16. 16.
    Strassman, M. and Weinhouse, S. (1953) Biosynthetic pathways. III. The biosynthesis of lysine Torulopsis utilis. J. Am. Chem. Soc. 75, 1680–1684.Google Scholar
  17. 17.
    Vogel, H. J. (1965) Lysine biosynthesis and evolution, in Handbook of Evolving Genes and Proteins (Bryson, V., ed.), Academic Press, New York, pp. 25–40.Google Scholar
  18. 18.
    Nishida, H., Nishiyama, M., Kobashi, N., Kosuge, T., Hoshino, T., and Yamane, H. (1999) A prokaryotic gene cluster involved in synthesis of lysine through the aminoadipate pathway: a key to the evolution of amino acid biosynthesis. Genome Res. 9, 1175–1183.PubMedGoogle Scholar
  19. 19.
    Cunin, R., Glandsorff, N., Pierard, A., and Stalon, V. (1986) Biosynthesis and metabolism of arginine in bacteria. Microbiol. Rev. 50, 314–352.PubMedGoogle Scholar
  20. 20.
    Jacq, C., Alt-Morbe, J., Andre, B., et al. (1997) The nucleotide sequence of saccharomyces cerevisiae chromosome IV. Nature 387, 75–78.PubMedGoogle Scholar
  21. 21.
    Philippsen, P., Kleine, K., Pohlmann, R., et al. (1997) The nucleotide sequence of Saccharomyces cerevisiae chromosome XIV and its evolutionary implications. Nature 387, 93–98.PubMedGoogle Scholar
  22. 22.
    Tettelin, H., Agostoni Carbone, M. L., Albermann, K., et al. (1997) The nucleotide sequence of Saccharomyces cerevisiae chromosome VII. Nature 387, 81–84.PubMedGoogle Scholar
  23. 23.
    Borell, C. W., Urrestarazu, L. A., and Bhattacharjee, J. K. (1984) Two unlinked lysine genes (LYS9 and LYS14) are required for the synthesis of saccharopine reductase in Saccharomyces cerevisiae. J. Bacteriol. 159, 429–432.PubMedGoogle Scholar
  24. 24.
    Wang, L., Okamoto, S., and Bhattacharjee, J. K. (1989) Cloning and physical characterization of linked lysine genes (LYS4, LYS15) of S. cerevisiae. Curr. Genet. 16, 7–12.PubMedGoogle Scholar
  25. 25.
    Urrestarazu, L. A., Borell, C. W., and Bhattacharjee, J. K. (1985) General and specific controls of lysine biosynthesis in Saccharomyces cerevisiae. Curr. Genet. 9, 341–344.PubMedGoogle Scholar
  26. 26.
    Irvin, S. D. and Bhattacharjee, J. K. (1998) A unique fungal lysine biosynthesis enzyme shares a common ancestor with tricarboxylic acid cycle and leucine biosynthetic enzymes found in diverse organisms. J. Mol. Evol. 46, 401–408.PubMedGoogle Scholar
  27. 27.
    Karsten, W. E. and Cook, P. F. (2000) Pyridine nucleotide-dependent β-hydroxyacid oxidative decarboxylases: an overview. Protein Pept. Lett. 7, 281–286.Google Scholar
  28. 28.
    Ye, Z. H., Garrad, R. C., Winston, M. K. and Bhattacharjee, J. K. (1991) Use of alpha-aminoadipate and lysine as sole nitrogen source by Schizosaccharomyces pombe and selected pathogenic fungi. J. Basic Microbiol. 31, 149–156.PubMedGoogle Scholar
  29. 29.
    Nishida, H. and Nishiyama, M. (2000) What is characteristic of fungal lysine synthesis through the α-aminoadipate pathway?. J. Mol. Evol. 51, 299–302.PubMedGoogle Scholar
  30. 30.
    Kosuge, T. and Hoshino, T. (1998) Lysine is synthesized through the α-aminoadipate pathway in Thermus thermophilus. FEMS Microbiol. Lett. 169, 361–367.PubMedGoogle Scholar
  31. 31.
    Kobashi, N., Nishiyama, M., and Tanokura, M. (1999) Aspartate kinase-independent lysine synthesis in an extremely thermophilic bacterium, Thermus thermophilus: lysine is synthesized via α-aminoadipic acid not via diaminopimelic acid. J. Bacteriol. 181, 1713–1718.PubMedGoogle Scholar
  32. 32.
    Baldwin, J. E., Shiau, C., Byford, M., and Schofield, C. J. (1994) Substrate specificity of l-delta-(alpha-aminoadipoyl)-l-cysteinyl-D-valine synthetase from Cephalosporium acremonium: demonstration of the structure of several unnatural tripeptide products. Biochem. J. 301, 367–372.PubMedGoogle Scholar
  33. 33.
    Palmer D. R., Balogh, H., Ma, G., Zhou, X., Marko, M., and Kaminskyj, S. G. (2004) Synthesis and antifungal properties of compounds which target the alpha-aminoadipate pathway. Pharmazie 59, 93–98.PubMedGoogle Scholar
  34. 34.
    Ramos, F., Dubois, E., and Piérard, A. (1988) Control of enzyme synthesis in the lysine biosynthetic pathway of Saccharomyces cerevisiae. Evidence for a regulatory role of gene LYS14. Eur. J. Biochem. 171, 171–176.PubMedGoogle Scholar
  35. 35.
    Wolfner, M., Yep, D., Messenguy, F., and Fink, G. R. (1975) Integration of amino acid biosynthesis into the cell cycle of Saccharomyces cerevisiae. J. Mol. Biol. 96, 273–290.PubMedGoogle Scholar
  36. 36.
    Becker, B., Feller, A., El Alami, M., Dubois, E., and Pierard, A. (1998) A nonameric core sequence is required upstream of the LYS genes of Saccharomyces cerevisiae for Lys14p-mediated activation and apparent repression by lysine. Mol. Microbiol. 29, 151–163.PubMedGoogle Scholar
  37. 37.
    Ramos, F., Verhasselt, P., Feller, A., et al. (1996) Identification of a gene encoding a homocitrate synthase isoenzyme of Saccharomyces cerevisiae. Yeast 12, 1315–1320.PubMedGoogle Scholar
  38. 38.
    Tucci, A. F. and Ceci, L. N. (1972) Homocitrate synthase from yeast. Arch. Biochem. Biophys. 153, 742–750.PubMedGoogle Scholar
  39. 39.
    Ramos, F., and Wiame, J. M. (1985) Mutation affecting the specific regulatory control of lysine biosynthetic enzymes in Saccharomyces cerevisiae. Mol. Gen. Genet. 200, 291–294.PubMedGoogle Scholar
  40. 40.
    Feller, A., Ramos, F., Piérard, A., and Bubois, E. (1999) In Saccharomyces cerevisiae, feedback inhibition of homocitrate synthase isoenzymes by lysine modulates the activation of LYS gene expression by Lys14p. Eur. J. Biochem. 261, 163–170.PubMedGoogle Scholar
  41. 41.
    Harrison, S. C. (1991) A structural taxonomy of DNA-binding domains. Nature 353, 715–719.PubMedGoogle Scholar
  42. 42.
    Vallee, B. L., Coleman, J. E., and Auld, D. S. (1991) Zinc fingers, zinc clusters, and zinc twists in DNA-binding protein domains. Proc. Natl. Acad. Sci. USA 88, 999–1003.PubMedGoogle Scholar
  43. 43.
    Marmorstein, R., Carey, M., Ptashne, M., and Harrison, S. C. (1992) DNA recognition by GAL4: structure of a protein-DNA complex. Nature 356, 408–414.PubMedGoogle Scholar
  44. 44.
    Marmorstein, R., and Harrison, S. C. (1994) Crystal structure of a PPR1-DNA complex: DNA recognition by proteins containing a Zn2Cys6 binuclear cluster. Genes Dev. 8, 2504–2512.PubMedGoogle Scholar
  45. 45.
    Schejerling, P. and Holmberg, S. (1996) Comparative amino acid sequence analysis of the C6 zinc cluster family of transcriptional regulators. Nucleic Acids Res. 24, 4599–4607.Google Scholar
  46. 46.
    Bañuelos, O., Casqueiro, J., Gutiérrez, S., and Mart (2000) Overexpression of the lys1 gene in Penicillium chrysogenum: homocitrate synthase levels, α-aminoadipic acid pool and penicillin production. Appl. Microbiol. Biotechnol. 54, 69–77.PubMedGoogle Scholar
  47. 47.
    Wulandari, A. P., Miyazaki, J., Kobashi, N., Nishiyama, M., Hoshino, T., and Yamane, H. (2002) Characterization of bacterial homocitrate synthase involved in lysine biosynthesis. FEBS Lett. 522, 35–40.PubMedGoogle Scholar
  48. 48.
    Andi, B., West, A. H., and Cook, P. F. (2005) Regulatory mechanism of histidine-tagged homocitrate synthase from Saccharomyces cerevisiae: I. Kinetic studies. J. Biol. Chem. 280, 31,624–31,632.Google Scholar
  49. 49.
    Andi, B. and Cook, P. F. (2005) Regulatory mechanism of histidine-tagged homocitrate synthase form Saccharomyces cerevisiae: II. Theory. J. Biol. Chem. 280, 31,633–31,640.Google Scholar
  50. 50.
    Friedrich, C. G. and Demain, A. L. (1977) Homocitrate synthase as the crucial site of the lysine effect on penicillin biosynthesis. J. Antibiot. 30, 760–761.PubMedGoogle Scholar
  51. 51.
    Somerson, N. L., Demain, A. L., and Nunheimer, T. D. (1961) Reversal of lysine inhibition of penicillin production by α-aminoadipic acid. Arch. Biochem. Biophys. 93, 238–241.Google Scholar
  52. 52.
    Luengo, J. M., Revilla, G., López, M. J., Villanueva, J. R., and Mart homocitrate synthase by lysine in Penicillium chrysogenum. J. Bacteriol. 144, 869–976.Google Scholar
  53. 53.
    Tracy, J. W. and Kohlhaw, G. B. (1975) Reversible, coenzyme-A-mediated inactivation of biosynthetic condensing enzymes in yeast: a possible regulatory mechanism. Proc. Nat. Acad. Sci. USA 72, 1802–1806.PubMedGoogle Scholar
  54. 54.
    Hampsey, D. M. and Kohlaw, G. B. (1981) Inactivation of yeast α-isopropyl malate synthase by CoA. J. Biol. Chem. 256, 3791–3796.PubMedGoogle Scholar
  55. 55.
    Tracy, J. W. and Kohlhaw, G. B. (1977) Evidence for two distinct CoA binding sites on yeast α-isopropylmalate synthase. J. Biol. Chem. 252 4085–4091.PubMedGoogle Scholar
  56. 56.
    Kohlhaw, G. B. (2003) Leucine biosynthesis in fungi: entering metabolism through the back door. Microbiol. Mol. Biol. Rev. 67, 1–15.PubMedGoogle Scholar
  57. 57.
    Tan-Wilson, A. and Kohlhaw, G. B. (1978) Specific, reversible inactivation of yeast β-hydroxy-β-methylglutaryl-CoA reductase by CoA. Biochem. Biophys. Res. Commun. 85, 70–76.PubMedGoogle Scholar
  58. 58.
    Gilbert, H. F. and Stewart, M. D. (1981) Inactivation of hydroxymethylglutaryl-CoA reductase from yeast by coenzyme A disulfide. J. Biol. Chem. 256, 1782–1785.PubMedGoogle Scholar
  59. 59.
    Li, J. J. (2003) Name Reactions: A Collection of Detailed Reaction Mechanism, 2nd ed., Springer, Berlin.Google Scholar
  60. 60.
    Alter, G. M., Casazza, J. P., Zhi, W., Memeth, P., Srere, P. A., and Evans, C. T. (1990) Mutation of essential catalytic residues in pig citrate synthase. Biochemistry 29, 7557–7563.PubMedGoogle Scholar
  61. 61.
    Karpusas, M., Branchaud, B., and Remington, S. J. (1990) Proposed mechanism for the condensation reaction of citrate synthase: 1.9 Å structure of the ternary complex with oxaloacetate and carboxymethyl coenzyme A. Biochemistry 29, 2213–2219.PubMedGoogle Scholar
  62. 62.
    Mulholland, A. J., Lyne, P. D., and Karplus, M. (2000) Ab initio QM/MM study of the citrate synthase mechanism: a low-barrier hydrogen bond is not involved. J. Am. Chem. Soc. 122, 534–535.Google Scholar
  63. 63.
    Evans, C. T., Kurz, L. C., Remington, S. J., and Srere, P. A. (1996) Active site mutants of pig citrate synthase: effects of mutations on the enzyme catalytic and structural properties. Biochemistry 35, 10,661–10,672.Google Scholar
  64. 64.
    Simth, C. V., Huang, C.-C., Miczak, A., Russell, D. G., Sacchettini, J. C., and Höner zu Bentrup, K. (2003) Biochemical and structural studies of malate synthase from Mycobacterium tuberculosis. J. Biol. Chem. 278, 1735–1743.Google Scholar
  65. 65.
    Anstrom, D. M., Kallio, K., and Remington, S. J. (2003) Structure of the Escherichia coli malate synthase G:pyruvate:acetyl-coenzyme A abortive ternary complex at 1.95 Å resolution. Protein Sci. 12, 1822–1832.PubMedGoogle Scholar
  66. 66.
    Howard, B. R., Endrizzi, J. A., and Remington, S. J. (2000) Crystal structure of Escherichia coli malate synthase G complexed with magnesium and glyoxylate at 2.0 Å resolution: mechanistic implications. Biochemistry 39, 3156–3168.PubMedGoogle Scholar
  67. 67.
    Koon, N., Squire, C. J., and Baker, E. N. (2004) Crystal structure of LeuA from Mycobacterium tuberculosis, a key enzyme in leucine biosynthesis. Proc. Nat. Acad. Sci. USA 101, 8295–8300.PubMedGoogle Scholar
  68. 68.
    Chen, S., Brockenbrough, J. S., Dove, J. E., and Aris, J. P. (1997) Homocitrate synthase is located in the nucleus in the yeast Saccharomyces cerevisiae. J. Biol. Chem. 272, 10,839–10,846.Google Scholar
  69. 69.
    Bañuelos, O., Casqueiro, J., Steidl, S., Gutirrez, S., Brakhage, A., and Martin, J. F. (2002) Subcellular localization of the homocitrate synthase in Penicillium chrysogenum. Mol. Genet. Genomics 266, 711–719.PubMedGoogle Scholar
  70. 70.
    Verhasselt, P., Voet, M., and Volckaert, G. (1995) New open reading frames, one of which is similar to the nifV gene of Azotobacter vinelandii, found on a 12.5 kbp fragment of chromosome IV of Saccharomyces cerevisiae. Yeast 11, 961–966.PubMedGoogle Scholar
  71. 71.
    Shah, V. K. and Brill, W. J. (1977) Isolation of an iron-molybdenum cofactor from nitrogenase. Proc. Natl. Acad. Sci. USA 74, 3249–3253.PubMedGoogle Scholar
  72. 72.
    Zheng, L. M., White, R. H., and Dean, D. R. (1997) Purification of the Azotobacter vinelandii nifV-encoded homocitrate synthase. J. Bacteriol. 179, 5963–5966.PubMedGoogle Scholar
  73. 73.
    Gaillardin, C. M., Poirier, L., and Heslot, H. (1976) A kinetic study of homocitrate synthase activity in the yeast Saccharomycopsis lipolytica. Biochim. Biophys. Acta 422, 390–406.PubMedGoogle Scholar
  74. 74.
    Andi, B., West, A. H., and Cook, P. F. (2004) Kinetic mechanism of histidine-tagged homocitrate synthase from Saccharomyces cerevisiae. Biochemistry 43, 11,790–11,795.Google Scholar
  75. 75.
    Voet, D. and Voet, J. G. (2004) Biochemistry, 3rd ed., John Wiley, New York.Google Scholar
  76. 76.
    Perez-campo, F.-M., Nicaud, J.-M., Gaillardin, C., and Dominguez, A. (1996) Cloning and sequencing of the LYS1 gene encoding homocitrate synthase in the yeast Yarrowia lipolytica. Yeast 12, 1459–1469.PubMedGoogle Scholar
  77. 77.
    Thomas, U., Kalyanpur, M. G., and Stevens, C. M. (1966) The absolute configuration of homocitric acid (2-hydroxy-1,2,4-butanetricarboxylic acid), an intermediate in lysine biosynthesis. Biochemistry 5, 2513–2516.PubMedGoogle Scholar
  78. 78.
    Copley, R. R. and Bork, P. (2000) Homology among (betaalpha) (8) barrels: implications for the evolution of metabolic pathways. J. Mol. Biol. 303, 627–640.PubMedGoogle Scholar
  79. 79.
    Vallee, B. L., and Auld, D. S. (1990) Active-site zinc ligands and activated H2O of zinc enzymes. Proc. Natl. Acad. Sci. USA 87, 220–224.PubMedGoogle Scholar
  80. 80.
    Vallee, B., and Auld, D. S. (1989) Short and long spacer sequences and other structural features of zinc binding sites in zinc enzymes. FEBS Lett. 257, 138–140.PubMedGoogle Scholar
  81. 81.
    Vallee, B., and Auld, D. S. (1990) Zinc coordination, function, and structure of zinc enzymes and other proteins. Biochemistry 29, 5647–5659.PubMedGoogle Scholar
  82. 82.
    Beinert, H., Kennedy, M. C., and Stout, C. D. (1996) Aconitase as iron-sulfur protein, enzyme, and iron-regulatory protein. Chem. Rev. 96, 2335–2373.PubMedGoogle Scholar
  83. 83.
    Grodsky, N. B., Soundar, S., and Colman, R. F. (2000) Evaluation by site-directed mutagenesis of aspartic acid residues in the metal site of pig heart NADP-dependent isociatrate dehydrogenase. Biochemistry 39, 2193–2200.PubMedGoogle Scholar
  84. 84.
    Matsuda, M. and Ogur, M. (1969) Separation and specificity of the yeast glutamate-α-ketoadipate transaminase. J. Biol. Chem. 244, 3352–3358.PubMedGoogle Scholar
  85. 85.
    Matsuda, M. and Ogur, M. (1969) Enzymatic and physiological properties of the yeast glutamate-α-ketoadipate transaminase. J. Biol. Chem. 244, 5153–5158.PubMedGoogle Scholar
  86. 86.
    Sagisaka, S. and Shimura, K. (1962) Studies in lysine biosynthesis. IV. Mechanism of activation and reduction of α-aminoadipic acid. J. Biochem. 52, 155–161.PubMedGoogle Scholar
  87. 87.
    Larson, R. L., Sandine, W. D., and Broquist, H. P. (1963) Enzymatic reduction of α-aminoadipic acid: relation to lysine biosynthesis. J. Biol. Chem. 238, 275–282.Google Scholar
  88. 88.
    Sinha, A. K. and Bhattacharjee, J. K. (1971) Lysine biosynthesis in Saccharomyces, conversion of α-aminoadipate into α-aminoadipic δ-semialdehyde. Biochem. J. 125, 743–749.PubMedGoogle Scholar
  89. 89.
    Suyarna, K., Seah, L., Bhattacharjee, V., and Bhattacharjee, J. K. (1998) Molecular analysis of the LYS2 gene of Candida albicans: homology to peptide antibiotic synthetases and the regulation of the α-amioadipate reductase. Curr. Genet. 33, 268–275.Google Scholar
  90. 90.
    Lambalot, R. H., Gehring, A. M., Flugel, R. S., et al. (1996) A new enzyme superfamily—the phosphopatetheinyl transferases. Chem. Biol. 3, 932–936.Google Scholar
  91. 91.
    Ehmann, D. E., Gehring, A. M., and Walsh, C. T. (1999) Lysine biosynthesis in Saccharomyces cerevisiae: mechanism of α-aminoadipate reductase (LYS2) involves posttranslational phosphopantetheinylation by LYS5. Biochemistry 38, 6171–6177.PubMedGoogle Scholar
  92. 92.
    Praphanphoj, V., Sacksteder, K. A., Gould, S. J., Thomas, G. H., and Geraghty, M. T. (2001) Identification of the α-aminoadipic semialdehyde dehydrogenase-phosphopantetheinyl transferase gene, the human ortholog of the yeast LYS5 gene. Mol. Genet. Metab. 72, 336–342.PubMedGoogle Scholar
  93. 93.
    Guo, S., Evans, S. A., Wilkes, M. B., and Bhattacharjee, J. K. (2001) Novel posttranslational activation of the LYS2-encoded α-aminoadipate reductase for biosynthesis of lysine and site-directed mutational analysis of conserved amino acid residues in the activation domain of Candida albicans. J. Bacteriol. 183, 7120–7125.PubMedGoogle Scholar
  94. 94.
    Brunhuber, N. M., and Blanchard, J. S. (1994) The biochemistry and enzymology of amino acid dehydrogenases. Crit. Rev. Biochem. Mol. Biol. 29, 415–467.PubMedGoogle Scholar
  95. 95.
    Weiss, P. M., Chen, C.-Y., Cleland, W. W., and Cook, P. F. (1998) Use of primary deuterium and 15N isotope effects to deduce the relative rates of steps in the mechanisms of alanine and glutamate dehydrogenases. Biochemistry 27, 4814–4822.Google Scholar
  96. 96.
    Rife, J. E., and Cleland, W. W. (1980a) Kinetic mechanism of glutamate dehydrogenase. Biochemistry 19, 2321–2328.PubMedGoogle Scholar
  97. 97.
    Schroder, I., Vadas, A., Johnson, E., Lim, S., and Monbouquette, H. G. (2004) A novel archaeal alanine dehydrogenase homologous to ornithine cyclodeaminase and μ-crystallin. J. Bacteriol. 186, 7680–7689.PubMedGoogle Scholar
  98. 98.
    Ohshima, T. and Soda, K. (1979) Purification and characterization of alanine dehydrogenase from Bacillus sphaericus. Eur. J. Biochem. 100, 29–39.Google Scholar
  99. 99.
    Alizade, M. A., Bressler, R., and Brendel, K. (1975) Stereochemistry of the hydrogen transfer to NAD catalyzed by (S)alanine dehydrogenase from Bacillus subtilis. Biochim. Biophys. Acta 397, 5–8.PubMedGoogle Scholar
  100. 100.
    Hashimoto, H., Misono, H., Nagata, S., and Nagasaki, S. (1989) Activation of l-lysine ε-dehydrogenase from Agrobacterium tumefaciens by several amino acids and monocarboxylates. J. Biochem. 106, 76–80.PubMedGoogle Scholar
  101. 101.
    Scapin, G., Reddy, S. G., and Blanchard, J. S. (1996) Three-dimensional structure of meso-diaminopimelic acid dehydrogenase from Corynebacterium glutamicum. Biochemistry 35, 13,540–13,551.Google Scholar
  102. 102.
    Johansson, E., Steffens, J. J., Lindqvist, Y., and Schneider, G. (2000) Crystal structure of saccharopine reductase from Magnaporthe grisea, an enzyme of the α-aminoadipate pathway of lysine biosynthesis. Struct. Fold. Des. 8, 1037–1047.Google Scholar
  103. 103.
    Fujioka, M. and Takata, Y. (1979) Stereospecificity of hydrogen transfer in the saccharopine dehydrogenase reaction. Biochim. Biophys. Acta 570, 210–212.PubMedGoogle Scholar
  104. 104.
    Sugimoto, K. and Fujioka, M. (1984) Chemical mechanism of saccharopine dehydrogenase (NAD+, l-lysine-forming) as deduced form initial rate pH studies. Arch. Biochem. Biophys. 230, 553–559.Google Scholar
  105. 105.
    Stillman, T. J., Baker, P. J., Britton, K. L., and Rice, D. W. (1993) Conformational flexibility in glutamate dehydrogenase. Role of water in substrate recognition and catalysis. J. Mol. Biol. 234, 1131–1139.PubMedGoogle Scholar
  106. 106.
    Baker, P. J., Turnbull, A. P., Sedelnikova, S. E., Stillman, T. J., and Rice, D. W. (1995) A role for quaternary structure in the substrate specificity of leucine dehydrogenase. Structure 3, 693–705.PubMedGoogle Scholar
  107. 107.
    Baker, P. J., Sawa, Y., Shibata, H., Sedelnikova, S. E., and Rice, D. W. (1998) Analysis of the structure and substrate binding of Phormidium lapideum alanine dehydrogenase. Nat. Struct. Biol. 5, 561–567.PubMedGoogle Scholar
  108. 108.
    Vanhooke, J. L., Thoden, J. B., Brunhuber, N. M. W., Blanchard, J. S., and Holden, H. M. (1999) Phenylalanine dehydrogenase from Rhodococcus sp. M4: high-resolution X-ray analyses of inhibitory ternary complexes reveal key features in the oxidative deamination mechanism. Biochemistry 38, 2326–2339.PubMedGoogle Scholar
  109. 109.
    Baker, P. J., Waugh, M. L., Wang, X.-G., et al. (1997) Determinants of the substrate specificity in the superfamily of amino acid dehydrogenases. Biochemistry 36, 16,109–16,115.Google Scholar
  110. 110.
    Jones, E. W. and Fink, G. R. (1982) Regulation of amino acid and nucleotide synthesis in yeast, in Molecular Biology of the Yeast Saccharomyces, Metabolism and Gene Regulation (Strathern, J. N., Jones, E. W., and Broach, J. R., eds.), Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, pp. 181–299.Google Scholar
  111. 111.
    Storts, D. R. and Bhattacharjee, J. K. (1987) Purification and properties of saccharopine dehydrogenase (glutamate forming) in the Saccharomyces cerevisiae lysine biosynthetic pathway. J. Bacteriol. 169, 416–418.PubMedGoogle Scholar
  112. 112.
    Jones, E. E. and Broquist, H. P. (1966) Saccharopine, an intermediate of the aminoadipic acid pathway of lysine biosynthesis. III. Aminoadipic semialdehyde-glutamate reductase. J. Biol. Chem. 241, 3430–3434.PubMedGoogle Scholar
  113. 113.
    Johansson, E., Steffens, J. J., Emptage, M., Lindqvist, Y., and Schneider, G. (2000) Cloning, expression, purification and crystallization of saccharopine reductase from Magnaporthe grisea. Acta Crystallogr. D Biol. Crystallogr. 56, 662–664.PubMedGoogle Scholar
  114. 114.
    Andi, B., Cook, P. F., and West, A. H. (2006) Crystal structure of the histidine-tagged saccharopine dehydrogenase (l-Glu forming) from Saccharomyces cerevisiae at 1.7Å resolution. Cell Biochem. Biophys. 46, 17–26.PubMedGoogle Scholar
  115. 115.
    Talbot, N. J. (1995) Having a blast: exploring the pathogenicity of Magnaporthe grisea. Trends Microbiol. 3, 9–16.PubMedGoogle Scholar
  116. 116.
    Rossmann, M. G., Liljas, A., Branden, C. I., and Banaszak, L. J. (1975) Evolutionary and structural relationship among dehydrogenases. Enzymes 11, 51–102.Google Scholar
  117. 117.
    Ogawa, H. and Fujioka, M. (1978) Purification and characterization of saccharopine dehydrogenase from baker's yeast. J. Biol. Chem. 253, 3666–3670.PubMedGoogle Scholar
  118. 118.
    Ogawa, H., Okamoto, M., and Fujioka, M. (1979) Chemical modification of the active site sulfhydryl group of saccharopine dehydrogenase (l-lysine-forming). J. Biol. Chem. 254, 7030–7035.PubMedGoogle Scholar
  119. 119.
    Ford, R. A., and Bhattacharjee, J. K. (1995) Molecular properties of the lys1+gene and the regulation of α-aminoadipate reductase in Schizosaccharomyces pombe. Curr. Genet. 28, 131–137.PubMedGoogle Scholar
  120. 120.
    Fujioka, M. and Nakatani, Y. (1974) Saccharopine dehydrogenase, a kinetic study of coenzyme binding. J. Biol. Chem. 249, 6886–6891.PubMedGoogle Scholar
  121. 121.
    Saunders, P. P. and Broquist, H. P. (1966) Saccharopine, an intermediate of the aminoadipic acid pathway of lysine biosynthesis, saccharopine dehydrogenase. J. Biol. Chem. 241, 3435–3440.PubMedGoogle Scholar
  122. 122.
    Fujioka, M. and Nakatani, Y. (1972) Saccharopine dehydrogenase, interaction with substrate analogues. Eur. J. Biochem. 25, 301–307.PubMedGoogle Scholar
  123. 123.
    Fujioka, M. and Tanaka, M. (1978) Enzymic and chemical synthesis of ε-N-(l-propionyl-2)-l-lysine. Eur. J. Biochem. 90, 297–300.PubMedGoogle Scholar
  124. 124.
    Cleland, W. W. (1963) The kinetics of enzyme-catalyzed reactions with two or more substrates. Biochim. Biophys. Acta 67, 173–187.PubMedGoogle Scholar
  125. 125.
    Fujioka, M. (1975) Saccharopine dehydrogenase, substrate inhibition studies. J. Biol. Chem. 250, 8986–8989.PubMedGoogle Scholar
  126. 126.
    Fujioka, M. and Nakatani, Y. (1970) A kinetic study of saccharopine dehydrogenase reaction. Eur. J. Biochem. 16, 180–186.PubMedGoogle Scholar
  127. 127.
    Sugimoto, K. and Fujioka, M. (1978) The reaction of pyruvate with saccharopine dehydrogenase. Eur. J. Biochem. 90, 301–307.PubMedGoogle Scholar
  128. 128.
    Fujioka, M., Takata, Y., Ogawa, H., and Okamoto, M. (1979) The inactivation of saccharopine dehydrogenase (l-lysine-forming) by diethyl pyrocarbonate. J. Biol. Chem. 255, 937–942.Google Scholar
  129. 129.
    Ogawa, H. and Fujioka, M. (1980) The reaction of pyridoxal-5′-phosphate with an essential lysine residue of saccharopine dehydrogenase (l-lysine-forming). J. Biol. Chem. 255, 7420–7425.PubMedGoogle Scholar
  130. 130.
    Fujioka, M. and Takata, Y. (1981) Role of arginine residue in saccharopine dehydrogenase (l-lysine-forming) from baker's yeast. Biochemistry 20, 468–472.PubMedGoogle Scholar
  131. 131.
    Ogawa, H., Hase, T., and Fujioka, M. (1980) Amino acid sequence of a peptide containing an essential cysteine residue of yeast saccharopine dehydrogenase (l-lysine-forming). Biochim. Biophys. Acta 623, 225–228.PubMedGoogle Scholar
  132. 132.
    Hammer, T., Bode, R., Schmidt, H., and Birnbaum, D. (1991) Distribution of three lysine-catabolizing enzymes in various yeast species. J. Basic Microbiol. 31, 43–49.Google Scholar

Copyright information

© Humana Press Inc 2006

Authors and Affiliations

  1. 1.Department of Chemistry and BiochemistryUniversity of OklahomaNorman

Personalised recommendations