Journal of Molecular Evolution

, Volume 41, Issue 6, pp 760–774 | Cite as

Molecular evolution of the histidine biosynthetic pathway

  • Renato Fani
  • Pietro Liò
  • Antonio Lazcano


The available sequences of genes encoding the enzymes associated with histidine biosynthesis suggest that this is an ancient metabolic pathway that was assembled prior to the diversification of the Bacteria, Archaea, and Eucarya. Paralogous duplications, gene elongation, and fusion events involving different his genes have played a major role in shaping this biosynthetic route. Evidence that the hisA and the hisF genes and their homologues are the result of two successive duplication events that apparently took place before the separation of the three cellular lineages is extended. These two successive gene duplication events as well as the homology between the hisH genes and the sequences encoding the TrpG-type amidotransferases support the idea that during the early stages of metabolic evolution at least parts of the histidine biosynthetic pathway were mediated by enzymes of broader substrate specificities. Maximum likelihood trees calculated for the available sequences of genes encoding these enzymes have been obtained. Their topologies support the possibility of an evolutionary proximity of archaebacteria with low GC Gram-positive bacteria. This observation is consistent with those detected by other workers using the sequences of heat-shock proteins (HSP70), glutamine synthetases, glutamate dehydrogenases, and carbamoylphosphate synthetases.

Key words

Histidine biosynthesis Evolution of metabolic pathways Molecular evolution 



amino acid


open reading frame


base pair


103 bp


carbamoyl phosphate synthetase (EC


glutamine amidotransferase


GMP synthetase (EC


4-amino-4-deoxychorismate synthase (EC 4.1.3-)


GTP synthetase (EC


5-aminoimidazole-4-carboxamide-l-β-d ribofuranosyl 5′-monophosphate






histidinol phosphate


imidazole acetol-phosphate


imidazole glycerol phosphate




N-[(5′-phosphoribulosyl) formimino]-5-aminoimidazole-4-carboxamide ribonucleotide


N1-[(5′-phosphoribosyl) formimino]-5-aminoimidazole-4-carboxamide ribonucleotide




restriction fragment length polymorphism


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Altboum Z, Gottlieb S, Lebens GA, Polacheck I, Segal E (1990) Isolation of the Candida albicans histidinol dehydrogenase (HIS4) gene and characterization of a histidine auxotroph. J Bacteriol 172: 3898–3904Google Scholar
  2. Arndt E (1990) Nucleotide sequence of four genes encoding ribosomal proteins from the “S10 and Spectinomycicn” operon equivalent region in the archaebacterium Halobacterium marismortui. FEBS Lett 267:193–198Google Scholar
  3. Auer J, Spicker G, Mayerhoff L, Puhler G, Bock A (1991) Organization and nucleotide sequence of a gene cluster comprising the translation elongation factor 1α from Sulfolobus acidocaldarius. System Appl Microbiol 14:14–22Google Scholar
  4. Bazzicalupo M, Fani R, Gallori E, Turbanti L, Polsinelli M (1987) Cloning of the histidine, pyrimidine and cysteine genes of Azospirillum brasilense: expression of pyrimidine and three clustered histidine genes in Escherichia coli. Mol Gen Genet 206:76–80Google Scholar
  5. Beckler GS, Reeve JN (1986) Conservation of primary structure in the hisI gene of the archaebacterium Methanococcus vannielii, the eubacterium Escherichia coli and the eucaryme Saccharomyces cerevisiae. Mol Gen Genet 204:133–140Google Scholar
  6. Belfaiza J, Parsot C, Martel A, Bouthier de la Tour C, Maragarita D, Cohen GN, Saint-Girons I (1986) Evolution in biosynthetic pathways: two enzymes catalyzing consecutive steps in methionine biosynthesis originate from a common ancestor and possess a similar regulatory region. Proc Natl Acad Sci USA 83:867–871Google Scholar
  7. Benachenhou-Lafha N, Forterre, P, Labedan B (1993) Evolution of glutamate dehydrogenase genes: evidence for two paralogous protein families and unusual branching patterns of the archaebacteria in the universal tree of life. J Mol Evol 36:335–346Google Scholar
  8. Brady DR, Houston LL (1973) Some properties of the catalytic sites of imidazoleglycerolephosphate dehydratase-histidinol phosphate phosphatase, a bifunctional enzyme from Salmonella typhimurium. J Biol Chem 248:2588–2592Google Scholar
  9. Brenner M, Ames BN (1971) The histidine operon and its regulation. In: Vogel HS (ed) Metabolic pathways, vol 5. Academic Press, New York, pp 349–387Google Scholar
  10. Broach JR (1981) Genes of Saccharomyces cerevisiae. In: Strathem IN, Jones EW, Broach JR (eds) The molecular biology of the yeast Saccharomyces: life cycle and inheritance. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, pp 653–727Google Scholar
  11. Brown JR, Masuchi Y, Robb FT, Doolittle WF (1994) Evolutionary relationships of bacterial and archaeal glutamine synthetase genes. J Mol Evol 38:566–576Google Scholar
  12. Bruni CB, Carlomagno MS, Formisano S, Paolella G (1986) Primary and secondary structural homologies between the HIS4 gene product of Saccharomyces cerevisiae and the hisIE and hisD gene products of Escherichia coli and Salmonella typhimurium. Mol Gen Genet 203:389–396Google Scholar
  13. Burke DH, Hearst JE, Sidow A (1993) Early evolution of photosynthesis: clues from nitrogenase and chlorophyll proteins. Proc Natl Acad Sci USA 90:7134–7138Google Scholar
  14. Bustos SA, Schaefer MR, Golden, SS (1990) Different and rapid responses of four cyanobacterial transcripts to changes in light intensity. J Bacteriol 172:1998–2004Google Scholar
  15. Carere A, Rossi S, Bignami M, Sermonti G (1973) An operon for histidine biosynthesis in Streptomyces coelicolor I. Genetic evidence. Mol Gen Genet 123:219–224Google Scholar
  16. Carlomagno MS, Chiarotti L, Alifano P, Nappo AG, Bruni CB (1988) Structure of the Salmonella typhimurium and Escherichia coli K-12 histidine operons. J Mol Biol 203:585–606Google Scholar
  17. Chumley FG, Roth JR (1981) Genetic fusions that place the lactose genes under histidine operon control. J Mol Biol 145:697–712Google Scholar
  18. Conover RK, Doolittle WF (1990) Characterization of a gene involved in histidine biosynthesis in Halobacterium (Haloferax)volcanii: isolation and rapid mapping by transformation of an auxotroph with cosmid DNA. J Bacteriol 172:3244–3249Google Scholar
  19. Crane DJ, Gould SJ (1994) The Pichia pastoris HIS4 gene: nucleotide sequence, creation of a non-reverting his4 mutant, and development of HIS4-based replicating and integrating plasmids. Curr Genet 26:443–450Google Scholar
  20. Cue D, Bekler G, Reeve J, Konisky J (1985) Structure and sequence divergence of two archaebacterial genes. Proc Natl Acad Sci U S A 82:4207–4211Google Scholar
  21. Davidson IN, Chen KC, Jamison RS, Musmanno LA, Kern CB (1993) The evolutionary history of the first three enzymes in pyrimidine biosynthesis. Bioessays 15:157–164Google Scholar
  22. Delorme C, Ehrlich SD, Renault P (1992) Histidine biosynthesis genes in Lactococcus lactis subsp. lactis. J Bacteriol 174:6571–6579Google Scholar
  23. Delorme C, Godon JJ, Ehrlich SD, Renault P (1993) Gene inactivation in Lactococcus lactis: histidine biosynthesis. J Bacteriol 175:4391–4399Google Scholar
  24. Denda K, Konishi J, Hajiro K, Oshima T, Dale T, Yosshida M (1990) Structure of an ATPase operon of an acidotermophilic archaebacterium, Sulfolobus acidocaldarius. J Biol Chem 265:21509–21513Google Scholar
  25. Derkos-Sojak V, Pigac J, Delic V (1985) Biochemical and genetic studies of a histidine regulatory mutant of Streptomyces coelicolor A3(2). J Basic Microbiol 25:479–485Google Scholar
  26. Donahue TF, Farabaugh PJ, Fink GR (1982) The nucleotide sequence of the His4 region of yeast. Gene 18:47–59Google Scholar
  27. Doolittle FW, Brown JR (1994) Tempo, mode, the progenote, and the universal root. Proc Natl Acad Sci USA 91:6721–6728Google Scholar
  28. Fani R, Bazzicalupo M, Damiani G, Bianchi A, Schipani C, Sgaramella V, Polsinelli M (1989) Cloning of the histidine genes of Azospirillum brasilense: organization of the ABFH gene cluster and nucleotide sequence of the hisB gene. Mol Gen Genet 216:224–229Google Scholar
  29. Fani R, Alifano P, Allotta G, Bazzicalupo M, Carlomagno MS, Gallori E, Rivellini F, Polsinelli M (1993) The histidine operon in Azospirillum brasilense: organization, nucleotide sequence and functional analysis. Res Microbiol 144:187–200Google Scholar
  30. Fani R, Liò P, Chiarelli I and Bazzicalupo M (1994) The evolution of the histidine biosynthetic genes in prokaryotes: a common ancestor for the hisA and hisF genes. J Mol Evol 38:489–495Google Scholar
  31. Fani R, Bandi C, Bazzicalupo M, Damiani G, Di Cello F, Fancelli S, Gallori E, Gerace L, Grifoni A, Liò P, Mori E (1995) Phylogenetic studies of the genus Azospirillum. In Proceedings of the NATO Advanced Research Workshop on Azospirillum and Related Microorganisms. Sarvar, Hungary, September 4–7, 1994 (in press)Google Scholar
  32. Felsenstein J (1981) Evolutionary trees from DNA sequences: a maximum likelihood approach. J Mol Evol 17:368–376PubMedGoogle Scholar
  33. Fink GR (1964) Gene-enzyme relations in histidine biosynthesis in yeast. Science 146:525–527Google Scholar
  34. Fischer RS, Bonner CA, Boone DR, Jensen RA (1993) Clues from a halophilic methanogen about aromatic amino acid biosynthesis in archaebacteria. Arch Microbiol 160:440–446Google Scholar
  35. Fox GE, Pechmann KR, Woese CR (1977) Comparative cataloging of 16S rRNA: a molecular approach to prokaryotic systematics. Int J Syst Bacteriol 27:44–57Google Scholar
  36. Glaser RD, Houston LL (1974) Subunit structure and photoxidation of yeast imidazole glycerolphosphate dehydratase. Biochemistry 13: 5145–5152Google Scholar
  37. Gogarten JP (1994) Which is the most conserved group of proteins? Homology, orthology, paralogy and the fusion of independent lineages. J Mol Evol 39:541–543Google Scholar
  38. Goldman GH, Demolder J, Dewaele S, Herrera-Estrella A, Geremia RA, Van Montagu M, Contreras R (1992) Molecular cloning of the imidazoleglycerolphosphate dehydratase gene of Trichoderma harzianum by genetic complementation in Saccharomyces cerevisiae using a direct expression vector. Mol Gen Genet 234:481–488Google Scholar
  39. Granick S (1965) Evolution of heme and chlorophyll. In: Bryson V, Vogel HJ (eds) Evolving genes and proteins. Academic Press, New York, pp 67–88Google Scholar
  40. Gupta RS, Golding GB (1993) Evolution of the HSP70 Gene and its implication regarding relationships between Archaebacteria, Eubacteria, and Eukaryotes. J Mol Evol 37:573–582Google Scholar
  41. Henner DJ, Band L, Flaggs G, Chen E (1986) The organization and nucleotide sequence of the Bacillus subtilis hisH, tyrA and aroE genes. Gene 49:147–152Google Scholar
  42. Higgins DG, Sharp PM (1988) CLUSTAL: a package for performing multiple sequence alignments on a microcomputer. Gene 73:237–244CrossRefPubMedGoogle Scholar
  43. Hikiji T, Okhuma M, Takagi M, Yano K (1989) An improved host-vector system for Candida maltosa using a gene isolated from its genome that complements the hiss mutation of Saccharomyces cerevisiae. Curr Genet 16:261–266Google Scholar
  44. Hinnebusch AG, Fink GR (1983) Repeated DNA sequences upstream from HIS1 also occur at several other co-regulated genes in Saccharomyces cerevisiae. J Biol Chem 258:5238–5247Google Scholar
  45. Hinshelwood S, Stoker NG (1992) Cloning of mycobacterial histidine synthesis genes by complementation of a Mycobacterium smegmatis auxotroph. Mol Microbiol 6:2887–2895Google Scholar
  46. Hopwood DA, Bibb M, Chater KF, Kieser T, Bruton CJ, Kieser HN, Lydiate D, Smith C, Ward JM, Schrempf H (1985) Genetic manipulation of Streptomyces. A laboratory manual. The John Innes Foundation, Norwich, p 356Google Scholar
  47. Horne M, Englert C, Wimmer C, Pfeifer F (1991) A DNA region of 9 Kbp contains all genes necessary for gas vesicle synthesis in halophilic archaebacteria. Mol Microbiol 5:1159–1174Google Scholar
  48. Horowitz NJ (1945) On the evolution of biochemical synthesis. Proc Natl Acad Sci USA 31:153–157Google Scholar
  49. Horowitz NJ (1965) The evolution of biochemical synthesis-retrospect and prospect. In: Bryson V, Vogel HJ (eds) Evolving genes and proteins. Academic Press, New York, pp 15–23Google Scholar
  50. Jensen RA (1976) Enzyme recruitment in evolution of new function. Annu Rev Microbiol 30:409–425Google Scholar
  51. Kaplan JB, Nichols BP (1983) Nucleotide sequence of Escherichia coli pabA and its evolutionary relationships to trp(G)D. J Mot Biol 168:451–468Google Scholar
  52. Klemm T, Davisson VJ (1993) Imidazole glycerol phosphate synthase: the glutamine amidotransferase in histidine biosynthesis. Biochemistry 32:5177–5186Google Scholar
  53. Kuenzler M, Balmelli T, Egli CM, Paravicini G, Braus GH (1993) Cloning, primary structure, and regulation of the HIS7 gene encoding a bifunctional glutamine amidotransferase: cyclase from Saccharomyces cerevisiae. J Bacteriol 175:5548–5558Google Scholar
  54. Kumada Y, Benson DR, Hillemann D, Hosted TJ, Rochford DA, Thompson CJ, Wohlleben W, Tateno Y (1993) Evolution of the glutamine synthase gene, one of the oldest and functioning genes. Proc Natl Acad Sci USA 90:3009–3013Google Scholar
  55. Labedan B, Riley M (1995) Widespread protein sequence similarities: origins of Escherichia coli genes. J Bacteriol 177:1585–1588Google Scholar
  56. Lazcano A, Fox GE, Otó J (1992) Life before DNA: the origin and evolution of early Archean cells. In: Mortlock RP (ed) The evolution of metabolic function. CRC Press, Boca Raton, FL, pp 237–339Google Scholar
  57. Lazcano A, Miller SL (1994) How long did it take for life to appear and evolve to cyanobacteria? J Mol Evol 39:546–554Google Scholar
  58. Legerton TL, Yanofsky C (1985) Cloning and characterization of the multifunctional his-3 gene of Neurospora crassa. Gene 39:129–140Google Scholar
  59. Li WH, Graur D (1991) Fundamentals of molecular evolution. Sinauer, Sunderland, MAGoogle Scholar
  60. Limauro D, Avitabile A, Cappellano C, Puglia AM, Bruni CB (1990) Cloning and characterization of the histidine biosynthetic gene cluster of Streptomyces coelicolor A3(2). Gene 90:31–41CrossRefGoogle Scholar
  61. Limauro D, Avitabile A, Puglia AM, Bruni CB (1992) Further characterization of the histidine gene cluster of Streptomyces coelicolor A3(2): nucleotide sequence and transcriptional analysis of hisD. Res Microbiol 143:683–693Google Scholar
  62. Loper JC (1961) Enzyme complementation in mixed extracts of mutants from the Salmonella histidine B locus. Proc Natl Acad Sci USA 47:1440–1450Google Scholar
  63. Maurel MC, Ninio J (1987) Catalysis by a prebiotic nucleotide analog of histidine. Biochimie 69:551–553Google Scholar
  64. Mozier NM, Walsh MP, Pearson JD (1991) Characterization of a novel zinc-binding site of protein kinase C inhibitor-1. FEBS Lett 279: 14–18Google Scholar
  65. Nagai A, Ward E, Beck J, Tada S, Chang JY, Scheidegger A, Ryals J (1991) Structural and functional conservation of histidinol dehydrogenate between plants and microbe. Proc Natl Acad Sci USA 88:4133–4137Google Scholar
  66. Nichols BP, Miozzari GF, van Cleemput M, Bennett GN, Yanofsky C (1980) Nucleotide sequence of the trpG regions of Escherichia coli, Shigella dysenteriae, Salmonella typhimurium and Serratia marcescens. J Mot Biol 142:503–517Google Scholar
  67. Nishiwaki K, Hayashi N, Irie S, Chung DH, Harashima S, Oshima Y (1987) Structure of the yeast HIS5 gene responsive to general control of amino acid biosynthesis. Mol Gen Genet 208:159–167Google Scholar
  68. Patee PA, Lee HC, Bannantine JP (1990) Genetic and physical mapping of Staphylococcus aureus. In: Novick RP (ed) Molecular biology of the Staphylococci. VCH Publishers, New York, pp 42–56Google Scholar
  69. Piette J, Nyunoya H, Lusty CJ, Cunin R, Weyens G, Crabeel M, Charlier D, Glansdorf N, Pierard A (1984) DNA sequences of the carA gene and the control region of carAB: tandem promoters, respectively controlled by arginine and the pyrimidines, regulate the synthesis of carbamoyl-phosphate synthetase in Escherichia coli K-12. Proc Natl Acad Sci USA 81:4134–4138Google Scholar
  70. Piggot PJ, Hoch JA (1985) Revised genetic linkage map of Bacillus subtilis. Microbiol Rev 49:158–179Google Scholar
  71. Rodriguez RL, West RW, Tait RC, Jaynes JM, Shanmugam KT (1981) Isolation and characterization of the hisG and hisD genes of Klebsiella pneumoniae. Gene 16:317–320Google Scholar
  72. Rodriguez RL, West RW (1984) Histidine operon control region of Klebsiella pneumoniae: analysis with an Escherichia coli promoter-probe plasmid vector. J Bacteriol 157:764–771Google Scholar
  73. Russi S, Carere A, Siracusano A, Ballio A (1973) An operon for histidine biosynthesis in Streptomyces coelicolor. II. Biochemical evidence. Mol Gen Genet 123:225–232Google Scholar
  74. Sampei G, Mizobuchi K (1989) The organization of purL gene encoding 5′ phosphoribosyl-formyl-glycinamide amidotransferase of Escherichia coli. J Biol Chem 264:21230–21238Google Scholar
  75. Schendel FJ, Mueller E, Stubbe J, Shiau A, Smith JM (1989) Formylglycinamide ribonucleotide synthetase from Escherichia coli: cloning, sequencing, overproduction, isolation and characterization. Biochemistry 28:2459–2471Google Scholar
  76. Shen C, Mills T, Oro J (1990a) Prebiotic synthesis of histidyl-histidine. J Mol Evol 31:175–179Google Scholar
  77. Shen C, Yang L, Miller SL, Oro J (1990b) Prebiotic synthesis of histidine. J Mol Evol 31:167–174Google Scholar
  78. Shen C, Lazcano A, Oro J (1990c) The enhancement activities of histidyl-histidine in some prebiotic reactions. J Mol Evol 31:445–452Google Scholar
  79. Sheridan RP, Venkataraghavan R (1992) A systematic search for protein signature sequences. Proteins 14:16–28Google Scholar
  80. Sthrul K (1985) Nucleotide sequence and transcriptional mapping of the yeast pet56-his3-dedl gene region. Nucleic Acids Res 13:8587–8601Google Scholar
  81. Tiboni O, Cammarano P, Sanangelantoni AM (1993) Cloning and sequencing of the gene encoding glutamine synthase I from the archaeum Pyrococcus woesei: anomalous phylogenies inferred from analysis of archaeal and bacterial glutamine synthase I sequences. J Bacteriol 175:2961–2969Google Scholar
  82. Tiedeman AA, Smith JM, Zalkin H (1985) Nucleotide sequence of the guaA gene encoding GMP synthetase of Escherichia coli K12. J Biol Chem 260:8676–8679Google Scholar
  83. Waley SG (1969) Some aspects of the evolution of metabolic pathways. Comp Biochem Physiol 30:1–7Google Scholar
  84. Weber AL, Miller SL (1981) Reasons for the occurrence of the twenty coded protein amino acids. J Mol Evol 17:273–284Google Scholar
  85. Weil C, Bekler G, Reeve J (1987) Structure and organization of the hisA gene of the thermophilic archaebacterium Methanococcus thermolithotrophicus. J Bacteriol 169:4857–4859Google Scholar
  86. Weinstock K, Strathern JN (1993) Molecular genetics in Saccharomyces klyyveri: The HIS3 homolog and its use as a selectable marker gene in S. kluyveri and Saccharomyces cerevisiae. Yeast 9:351–361Google Scholar
  87. Weir B (1990) Genetic data analysis. Sinauer Press, Sunderland.Google Scholar
  88. Weng M, Makaroff CA, Zalkin H (1986) Nucleotide sequence of Escherichia coli pyrG encoding CTP synthetase. J Biol Chem 261: 5568–5574Google Scholar
  89. White HB (1976) Coenzymes as fossils of an earlier metabolic state. J Mol Evol 7:101–117Google Scholar
  90. White DH, Erickson JC (1980) Catalysis of peptide bond formation by histidyl-histidine in a fluctuating clay environment. J Mol Evol 16:279–290Google Scholar
  91. Winkler ME (1987) Biosynthesis of histidine. In: Neidhardt FC, Ingraham JL, Low KB, Magasanik B, Schaechter M, Humbarger HE (eds) Escherichia coli and Salmonella typhimurium: cellular and molecular biology, vol 1 American Society for Microbiology, Washington, DC, pp 395–411Google Scholar
  92. Ycas M (1974) On the earlier states of the biochemical system. J Theor Biol 44:145–160Google Scholar
  93. Zalkin H (1985) Glutamine amidotransferases. Methods Enzymol 113: 263–264Google Scholar
  94. Zillig W (1991) Comparative biochemistry of Archaea and Bacteria. Curr Opin Genet Dev 1:544–551Google Scholar
  95. Zillig W, Palm P, Reiter WD, Gropp F, Pulher G, Klenk HP (1988) Comparative evaluation of gene expression in archaebacteria. Eur J Biochem 173:473–482Google Scholar

Copyright information

© Springer-Verlag New York Inc 1995

Authors and Affiliations

  • Renato Fani
    • 1
  • Pietro Liò
    • 1
  • Antonio Lazcano
    • 2
  1. 1.Dipartimento di Biologia Animale e GeneticaUniversità degli Studi di FirenzeFirenzeItaly
  2. 2.Facultad de CienciasUniversidad Nacional Autónoma de MéxicoMéxicoMexico

Personalised recommendations