Abstract
The bal, cep, dbv, sta and tcp gene clusters specify the biosynthesis of the glycopeptide antibiotics balhimycin, chloroeremomycin, A40926, A47934 and teicoplanin, respectively. These structurally related compounds share a similar mechanism of action in their inhibition of bacterial cell wall formation. Comparative sequence analysis was performed on the five gene clusters. Extensive conserved synteny was observed between the bal and cep clusters, which direct the synthesis of very similar compounds but originate from two different species of the genus Amycolatopsis. All other cluster pairs show a limited degree of conserved synteny, involving biosynthetically functional gene cassettes: these include those involved in the synthesis of the carbon backbone of two non-proteinogenic amino acids; in the linkage of amino acids 1–3 and 4–7 in the heptapeptide; and in the formation of the aromatic cross-links. Furthermore, these segments of conserved synteny are often preceded by conserved intergenic regions. Phylogenetic analysis of protein families shows several instances in which relatedness in the chemical structure of the glycopeptides is not reflected in the extent of the relationship of the corresponding polypeptides. Coherent branchings are observed for all polypeptides encoded by the syntenous gene cassettes. These results suggest that the acquisition of distinct, functional genetic elements has played a significant role in the evolution of glycopeptide gene clusters, giving them a mosaic structure. In addition, the synthesis of the structurally similar compounds A40926 and teicoplanin appears as the result of convergent evolution.
Similar content being viewed by others
References
Aparicio JF, Caffrey P, Gil JA, Zotchev SB (2003) Polyene antibiotic biosynthesis gene clusters. Appl Microbiol Biotechnol 61:179–188
Bentley SD et al (2002) Complete genome sequence of the model actinomycete Streptomyces coelicolor A3(2). Nature 417:141–147
Challis GL, Hopwood DA (2003) Synergy and contingency as driving forces for the evolution of multiple secondary metabolite production by Streptomyces species. Proc Natl Acad Sci USA 100:14555–14561
Challis GL, Ravel J (2000) Coelichelin, a new peptide siderophore encoded by the Streptomyces coelicolor genome: structure prediction from the sequence of its non-ribosomal peptide synthetase. FEMS Microbiol Lett 187:111–114
Chiu HT, Hubbard BK, Shah AN, Eide J, Fredenburg RA, Walsh CT, Khosla C (2001) Molecular cloning and sequence analysis of the complestatin biosynthetic gene cluster. Proc Natl Acad Sci USA 98:8548–8553
Christiansen G, Fastner J, Erhard M, Börner T, Dittmann E (2003) Microcystin biosynthesis in Planktothrix: genes, evolution, and manipulation. J Bacteriol 185:564–572
Egan S, Wiener P, Kallifidas D, Wellington EM (2001) Phylogeny of Streptomyces species and evidence for horizontal transfer of entire and partial antibiotic gene clusters. Antonie Van Leeuwenhoek 79:127–133
Hong H-J, Hutchings MI, Neu JM, Wright GD, Paget MS, Buttner MJ (2004) Characterization of an inducible vancomycin resistance system in Streptomyces coelicolor reveals a novel gene (vanK) required for drug resistance. Mol Microbiol 52:1107–1121
Hubbard BK, Walsh CT (2003) Vancomycin assembly: nature’s way. Angew Chem Int Ed Engl 42:730–765
Krzywinska E, Krzywinski J, Schorey JS (2004) Naturally occurring horizontal gene transfer and homologous recombination in Mycobacterium. Microbiology 150:1707–1712
Lancini G, Cavalleri B (1997) Glycopeptide antibiotics (dalbaheptides). In: Kleinkauf H, von Dohren H (eds) Biotechnology, vol 7. VCH, Weinheim Germany, pp369–396
Li S-M, Heide L (2005) New aminocoumarin antibiotics from genetically engineered Streptomyces strains. Curr Med Chem 12:763–771
Li T-L, Huang F, Haydock SF, Mironenko T, Leadlay PF, Spencer JB (2004) Biosynthetic gene cluster of the glycopeptide antibiotic teicoplanin: characterization of two glycosyltransferases and the key acyltransferase. Chem Biol 11:107–119
Liu W, Christenson SD, Standage S, Shen B (2002) Biosynthesis of the enediyne antitumor antibiotic C-1027. Science 297:1170–1173
Lopez JV (2003) Naturally mosaic operons for secondary metabolite biosynthesis: variability and putative horizontal transfer of discrete catalytic domains of the epothilone polyketide synthase locus. Mol Genet Genomics 270:420–431
Menendez N, Nur-e-Alam M, Brana AF, Rohr J, Salas JA, Mendez C (2004) Biosynthesis of the antitumor chromomycin A3 in Streptomyces grisues: analysis of the gene cluster and rational design of novel chromomycin analogs. Chem Biol 11:21–32
Metsa-Ketela M, Halo L, Munukka E, Hakala J, Mantsala P, Ylihonko K (2002) Molecular evolution of aromatic polyketides and comparative sequence analysis of polyketide ketosynthase and 16S ribosomal DNA genes from various streptomyces species. Appl Environ Microbiol 68:4472–4479
Moffitt MC, Neilan BA (2004) Characterization of the nodularin synthetase gene cluster and proposed theory of the evolution of cyanobacterial hepatotoxins. Appl Environ Microbiol 70:6353–6362
Omura S, Ikeda H, Ishikawa J, Hanamoto A, Takahashi C, Shinose M, Takahashi Y, Horikawa H, Nakazawa H, Osonoe T, Kikuchi H, Shiba T, Sakaki Y, Hattori M (2001) Genome sequence of an industrial microorganism Streptomyces avermitilis: deducing the ability of producing secondary metabolites. Proc Natl Acad Sci USA 98:12215–12220
Otsuka M, Ichinose K, Fujii I, Ebizuka Y (2004) Cloning, sequencing, and functional analysis of an iterative type I polyketide synthase gene cluster for biosynthesis of the antitumor chlorinated polyenone neocarzilin in “Streptomyces carzinostaticus”. Antimicrob Agents Chemother 48:3468–3476
Piel J, Hofer I, Hui D (2004) Evidence for a symbiosis island involved in horizontal acquisition of pederin biosynthetic capabilities by the bacterial symbiont of Paederus fuscipes beetles. J Bacteriol 186:1280–1286
Pootoolal J, Thomas MG, Marshall CG, Neu JM, Hubbard BK, Walsh CT, Wright GD (2002) Assembling the glycopeptide antibiotic scaffold: the biosynthesis of A47934 from Streptomyces toyocaensis NRRL15009. Proc Natl Acad Sci USA 99:8962–8967
Rantala A, Fewer DP, Hisbergues M, Rouhiainen L, Vaitomaa J, Borner T, Sivonen K (2004) Phylogenetic evidence for the early evolution of microcystin synthesis. Proc Natl Acad Sci USA 101:568–573
Recktenwald J, Shawky R, Puk O, Pfennig F, Keller U, Wohlleben W, Pelzer S (2002) Nonribosomal biosynthesis of vancomycin-type antibiotics: a heptapeptide backbone and eight peptide synthetase modules. Microbiology 148:1105–1118
Sosio M, Bossi E, Bianchi A, Donadio S (2000) Multiple peptide synthetase gene clusters in actinomycetes. Mol Gen Genet 264:213–221
Sosio M, Stinchi S, Beltrametti F, Lazzarini A, Donadio S (2003) The gene cluster for the biosynthesis of the glycopeptide antibiotic A40926 by Nonomuraea species. Chem Biol 10:541–549
Sosio M, Kloosterman H, Bianchi A, De Vreugd P, Dijkhuizen L, Donadio S (2004) Organization of the teicoplanin gene cluster in Actinoplanes teichomyceticus. Microbiology 150:95–102
Süßmuth RD, Wohlleben W (2003) The biosynthesis of glycopeptide antibiotics—a model for complex, non-ribosomally synthesized, peptidic secondary metabolites. Appl Microbiol Biotechnol 63:344–350
Van Wageningen AM, Kirkpatrick PN, Williams DH, Harris BR, Kershaw JK, Lennard NJ, Jones M, Jones SJ, Solenberg PJ (1998) Sequencing and analysis of genes involved in the biosynthesis of a vancomycin group antibiotic. Chem Biol 5:155–162
Walsh C (2003) Antibiotics: actions, origins, resistance. ASM Press, Washington, DC
Wink JM, Kroppenstedt RM, Ganguli BN, Nadkarni SR, Schumann P, Seibert G, Stackebrandt E (2003) Three new antibiotic producing species of the genus Amycolatopsis, Amycolatopsis balhimycina sp. nov., A. tolypomycina sp. nov., A. vancoresmycina sp. nov., and description of Amycolatopsis keratiniphila subsp. keratiniphila subsp. nov., and A. keratiniphila subsp. nogabecina subsp. nov. Syst Appl Microbiol 26:38–46
Acknowledgements
We are grateful to Giancarlo Lancini for valuable discussions. This work was partially supported by grants from the EU (QLK3-1999-00650 and LSHG-CT-2003-503491).
Author information
Authors and Affiliations
Corresponding author
Additional information
Communicated by W. Goebel
Rights and permissions
About this article
Cite this article
Donadio, S., Sosio, M., Stegmann, E. et al. Comparative analysis and insights into the evolution of gene clusters for glycopeptide antibiotic biosynthesis. Mol Genet Genomics 274, 40–50 (2005). https://doi.org/10.1007/s00438-005-1156-3
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00438-005-1156-3