Skip to main content
SpringerLink
Log in

Molecular evolution of the histidine biosynthetic pathway

  • Articles
  • Published:
Journal of Molecular Evolution Aims and scope Submit manuscript

Abstract

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

Abbreviations

as:

amino acid

ORF:

open reading frame

bp:

base pair

kb:

103 bp

CarA:

carbamoyl phosphate synthetase (EC 6.3.5.5)

GAT:

glutamine amidotransferase

GuaA:

GMP synthetase (EC 6.3.4.1)

PabA:

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

PyrG:

GTP synthetase (EC 6.3.4.2)

AICAR:

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

HAL:

l-histidinal

HOL:

l-histidinol

HP:

histidinol phosphate

IAP:

imidazole acetol-phosphate

IGP:

imidazole glycerol phosphate

PR:

phosphoribosyl

PRFAR:

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

5′-ProFAR:

N 1-[(5′-phosphoribosyl) formimino]-5-aminoimidazole-4-carboxamide ribonucleotide

PRPP:

phosphoribosyl-pyrophosphate

RFLP:

restriction fragment length polymorphism

References

  • 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: 3898–3904

    Google Scholar 

  • 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 267:193–198

    Google Scholar 

  • 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 14:14–22

    Google Scholar 

  • 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 206:76–80

    Google Scholar 

  • 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 204:133–140

    Google Scholar 

  • 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 83:867–871

    Google Scholar 

  • 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 36:335–346

    Google Scholar 

  • 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 248:2588–2592

    Google Scholar 

  • Brenner M, Ames BN (1971) The histidine operon and its regulation. In: Vogel HS (ed) Metabolic pathways, vol 5. Academic Press, New York, pp 349–387

    Google Scholar 

  • 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 653–727

    Google Scholar 

  • Brown JR, Masuchi Y, Robb FT, Doolittle WF (1994) Evolutionary relationships of bacterial and archaeal glutamine synthetase genes. J Mol Evol 38:566–576

    Google Scholar 

  • 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 203:389–396

    Google Scholar 

  • Burke DH, Hearst JE, Sidow A (1993) Early evolution of photosynthesis: clues from nitrogenase and chlorophyll proteins. Proc Natl Acad Sci USA 90:7134–7138

    Google Scholar 

  • Bustos SA, Schaefer MR, Golden, SS (1990) Different and rapid responses of four cyanobacterial transcripts to changes in light intensity. J Bacteriol 172:1998–2004

    Google Scholar 

  • Carere A, Rossi S, Bignami M, Sermonti G (1973) An operon for histidine biosynthesis in Streptomyces coelicolor I. Genetic evidence. Mol Gen Genet 123:219–224

    Google Scholar 

  • 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 203:585–606

    Google Scholar 

  • Chumley FG, Roth JR (1981) Genetic fusions that place the lactose genes under histidine operon control. J Mol Biol 145:697–712

    Google Scholar 

  • 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 172:3244–3249

    Google Scholar 

  • 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 26:443–450

    Google Scholar 

  • Cue D, Bekler G, Reeve J, Konisky J (1985) Structure and sequence divergence of two archaebacterial genes. Proc Natl Acad Sci U S A 82:4207–4211

    Google Scholar 

  • Davidson IN, Chen KC, Jamison RS, Musmanno LA, Kern CB (1993) The evolutionary history of the first three enzymes in pyrimidine biosynthesis. Bioessays 15:157–164

    Google Scholar 

  • Delorme C, Ehrlich SD, Renault P (1992) Histidine biosynthesis genes in Lactococcus lactis subsp. lactis. J Bacteriol 174:6571–6579

    Google Scholar 

  • Delorme C, Godon JJ, Ehrlich SD, Renault P (1993) Gene inactivation in Lactococcus lactis: histidine biosynthesis. J Bacteriol 175:4391–4399

    Google Scholar 

  • 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 265:21509–21513

    Google Scholar 

  • 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 25:479–485

    Google Scholar 

  • Donahue TF, Farabaugh PJ, Fink GR (1982) The nucleotide sequence of the His4 region of yeast. Gene 18:47–59

    Google Scholar 

  • Doolittle FW, Brown JR (1994) Tempo, mode, the progenote, and the universal root. Proc Natl Acad Sci USA 91:6721–6728

    Google Scholar 

  • 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 216:224–229

    Google Scholar 

  • 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 144:187–200

    Google Scholar 

  • 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 38:489–495

    Google Scholar 

  • 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)

  • Felsenstein J (1981) Evolutionary trees from DNA sequences: a maximum likelihood approach. J Mol Evol 17:368–376

    CAS  PubMed  Google Scholar 

  • Fink GR (1964) Gene-enzyme relations in histidine biosynthesis in yeast. Science 146:525–527

    Google Scholar 

  • Fischer RS, Bonner CA, Boone DR, Jensen RA (1993) Clues from a halophilic methanogen about aromatic amino acid biosynthesis in archaebacteria. Arch Microbiol 160:440–446

    Google Scholar 

  • Fox GE, Pechmann KR, Woese CR (1977) Comparative cataloging of 16S rRNA: a molecular approach to prokaryotic systematics. Int J Syst Bacteriol 27:44–57

    Google Scholar 

  • Glaser RD, Houston LL (1974) Subunit structure and photoxidation of yeast imidazole glycerolphosphate dehydratase. Biochemistry 13: 5145–5152

    Google Scholar 

  • Gogarten JP (1994) Which is the most conserved group of proteins? Homology, orthology, paralogy and the fusion of independent lineages. J Mol Evol 39:541–543

    Google Scholar 

  • 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 234:481–488

    Google Scholar 

  • Granick S (1965) Evolution of heme and chlorophyll. In: Bryson V, Vogel HJ (eds) Evolving genes and proteins. Academic Press, New York, pp 67–88

    Google Scholar 

  • Gupta RS, Golding GB (1993) Evolution of the HSP70 Gene and its implication regarding relationships between Archaebacteria, Eubacteria, and Eukaryotes. J Mol Evol 37:573–582

    Google Scholar 

  • Henner DJ, Band L, Flaggs G, Chen E (1986) The organization and nucleotide sequence of the Bacillus subtilis hisH, tyrA and aroE genes. Gene 49:147–152

    Google Scholar 

  • Higgins DG, Sharp PM (1988) CLUSTAL: a package for performing multiple sequence alignments on a microcomputer. Gene 73:237–244

    Article  CAS  PubMed  Google Scholar 

  • 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 16:261–266

    Google Scholar 

  • 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 258:5238–5247

    Google Scholar 

  • Hinshelwood S, Stoker NG (1992) Cloning of mycobacterial histidine synthesis genes by complementation of a Mycobacterium smegmatis auxotroph. Mol Microbiol 6:2887–2895

    Google Scholar 

  • 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 356

    Google Scholar 

  • 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 5:1159–1174

    Google Scholar 

  • Horowitz NJ (1945) On the evolution of biochemical synthesis. Proc Natl Acad Sci USA 31:153–157

    Google Scholar 

  • 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 15–23

    Google Scholar 

  • Jensen RA (1976) Enzyme recruitment in evolution of new function. Annu Rev Microbiol 30:409–425

    Google Scholar 

  • Kaplan JB, Nichols BP (1983) Nucleotide sequence of Escherichia coli pabA and its evolutionary relationships to trp(G)D. J Mot Biol 168:451–468

    Google Scholar 

  • Klemm T, Davisson VJ (1993) Imidazole glycerol phosphate synthase: the glutamine amidotransferase in histidine biosynthesis. Biochemistry 32:5177–5186

    Google Scholar 

  • 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 175:5548–5558

    Google Scholar 

  • 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 90:3009–3013

    Google Scholar 

  • Labedan B, Riley M (1995) Widespread protein sequence similarities: origins of Escherichia coli genes. J Bacteriol 177:1585–1588

    Google Scholar 

  • 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 237–339

    Google Scholar 

  • Lazcano A, Miller SL (1994) How long did it take for life to appear and evolve to cyanobacteria? J Mol Evol 39:546–554

    Google Scholar 

  • Legerton TL, Yanofsky C (1985) Cloning and characterization of the multifunctional his-3 gene of Neurospora crassa. Gene 39:129–140

    Google Scholar 

  • Li WH, Graur D (1991) Fundamentals of molecular evolution. Sinauer, Sunderland, MA

    Google Scholar 

  • 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 90:31–41

    Article  Google Scholar 

  • 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 143:683–693

    Google Scholar 

  • Loper JC (1961) Enzyme complementation in mixed extracts of mutants from the Salmonella histidine B locus. Proc Natl Acad Sci USA 47:1440–1450

    Google Scholar 

  • Maurel MC, Ninio J (1987) Catalysis by a prebiotic nucleotide analog of histidine. Biochimie 69:551–553

    Google Scholar 

  • Mozier NM, Walsh MP, Pearson JD (1991) Characterization of a novel zinc-binding site of protein kinase C inhibitor-1. FEBS Lett 279: 14–18

    Google Scholar 

  • 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 88:4133–4137

    Google Scholar 

  • 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 142:503–517

    Google Scholar 

  • 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 208:159–167

    Google Scholar 

  • 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 42–56

    Google Scholar 

  • 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 81:4134–4138

    Google Scholar 

  • Piggot PJ, Hoch JA (1985) Revised genetic linkage map of Bacillus subtilis. Microbiol Rev 49:158–179

    Google Scholar 

  • Rodriguez RL, West RW, Tait RC, Jaynes JM, Shanmugam KT (1981) Isolation and characterization of the hisG and hisD genes of Klebsiella pneumoniae. Gene 16:317–320

    Google Scholar 

  • Rodriguez RL, West RW (1984) Histidine operon control region of Klebsiella pneumoniae: analysis with an Escherichia coli promoter-probe plasmid vector. J Bacteriol 157:764–771

    Google Scholar 

  • Russi S, Carere A, Siracusano A, Ballio A (1973) An operon for histidine biosynthesis in Streptomyces coelicolor. II. Biochemical evidence. Mol Gen Genet 123:225–232

    Google Scholar 

  • Sampei G, Mizobuchi K (1989) The organization of purL gene encoding 5′ phosphoribosyl-formyl-glycinamide amidotransferase of Escherichia coli. J Biol Chem 264:21230–21238

    Google Scholar 

  • Schendel FJ, Mueller E, Stubbe J, Shiau A, Smith JM (1989) Formylglycinamide ribonucleotide synthetase from Escherichia coli: cloning, sequencing, overproduction, isolation and characterization. Biochemistry 28:2459–2471

    Google Scholar 

  • Shen C, Mills T, Oro J (1990a) Prebiotic synthesis of histidyl-histidine. J Mol Evol 31:175–179

    Google Scholar 

  • Shen C, Yang L, Miller SL, Oro J (1990b) Prebiotic synthesis of histidine. J Mol Evol 31:167–174

    Google Scholar 

  • Shen C, Lazcano A, Oro J (1990c) The enhancement activities of histidyl-histidine in some prebiotic reactions. J Mol Evol 31:445–452

    Google Scholar 

  • Sheridan RP, Venkataraghavan R (1992) A systematic search for protein signature sequences. Proteins 14:16–28

    Google Scholar 

  • Sthrul K (1985) Nucleotide sequence and transcriptional mapping of the yeast pet56-his3-dedl gene region. Nucleic Acids Res 13:8587–8601

    Google Scholar 

  • 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 175:2961–2969

    Google Scholar 

  • Tiedeman AA, Smith JM, Zalkin H (1985) Nucleotide sequence of the guaA gene encoding GMP synthetase of Escherichia coli K12. J Biol Chem 260:8676–8679

    Google Scholar 

  • Waley SG (1969) Some aspects of the evolution of metabolic pathways. Comp Biochem Physiol 30:1–7

    Google Scholar 

  • Weber AL, Miller SL (1981) Reasons for the occurrence of the twenty coded protein amino acids. J Mol Evol 17:273–284

    Google Scholar 

  • Weil C, Bekler G, Reeve J (1987) Structure and organization of the hisA gene of the thermophilic archaebacterium Methanococcus thermolithotrophicus. J Bacteriol 169:4857–4859

    Google Scholar 

  • 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 9:351–361

    Google Scholar 

  • Weir B (1990) Genetic data analysis. Sinauer Press, Sunderland.

    Google Scholar 

  • Weng M, Makaroff CA, Zalkin H (1986) Nucleotide sequence of Escherichia coli pyrG encoding CTP synthetase. J Biol Chem 261: 5568–5574

    Google Scholar 

  • White HB (1976) Coenzymes as fossils of an earlier metabolic state. J Mol Evol 7:101–117

    Google Scholar 

  • White DH, Erickson JC (1980) Catalysis of peptide bond formation by histidyl-histidine in a fluctuating clay environment. J Mol Evol 16:279–290

    Google Scholar 

  • 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 395–411

    Google Scholar 

  • Ycas M (1974) On the earlier states of the biochemical system. J Theor Biol 44:145–160

    Google Scholar 

  • Zalkin H (1985) Glutamine amidotransferases. Methods Enzymol 113: 263–264

    Google Scholar 

  • Zillig W (1991) Comparative biochemistry of Archaea and Bacteria. Curr Opin Genet Dev 1:544–551

    Google Scholar 

  • Zillig W, Palm P, Reiter WD, Gropp F, Pulher G, Klenk HP (1988) Comparative evaluation of gene expression in archaebacteria. Eur J Biochem 173:473–482

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Dipartimento di Biologia Animale e Genetica, Università degli Studi di Firenze, Via Romana 17, I-50125, Firenze, Italy

    Renato Fani & Pietro Liò

  2. Facultad de Ciencias, Universidad Nacional Autónoma de México, Apartado Postal 70-407, Cd Universitaria, 04510, D.F., México, Mexico

    Antonio Lazcano

Authors
  1. Renato Fani
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Pietro Liò
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Antonio Lazcano
    View author publications

    You can also search for this author in PubMed Google Scholar

Additional information

Correspondence to: R. Fani

Rights and permissions

Reprints and permissions

About this article

Cite this article

Fani, R., Liò, P. & Lazcano, A. Molecular evolution of the histidine biosynthetic pathway. J Mol Evol 41, 760–774 (1995). https://doi.org/10.1007/BF00173156

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00173156

Key words

Search

Navigation