Exploiting the genetic potential of polyketide producing streptomycetes

Weber, Tilmann; Welzel, Katrin; Pelzer, Stefan; Vente, Andreas; Wohlleben, Wolfgang

doi:10.1016/j.jbiotec.2003.08.004

Cited by 131 publications

(86 citation statements)

References 76 publications

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“…Over 80% of these natural products were derived from fungi and actinomycetes (31). Recent studies showed the rich sources of nonribosomal peptides and polyketides in bacterial lineages of myxobacteria (18), pseudomonads (32), cyanobacteria (17), and streptomycetes (33). Genomic analysis further revealed the presence of NRPSs and PKSs in archaea (22), metazoa (23), and dinoflagellates (24).…”

Section: Discussionmentioning

confidence: 99%

Atlas of nonribosomal peptide and polyketide biosynthetic pathways reveals common occurrence of nonmodular enzymes

Wang¹,

Fewer²,

Holm

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

293

263

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Nonribosomal peptides and polyketides are a diverse group of natural products with complex chemical structures and enormous pharmaceutical potential. They are synthesized on modular nonribosomal peptide synthetase (NRPS) and polyketide synthase (PKS) enzyme complexes by a conserved thiotemplate mechanism. Here, we report the widespread occurrence of NRPS and PKS genetic machinery across the three domains of life with the discovery of 3,339 gene clusters from 991 organisms, by examining a total of 2,699 genomes. These gene clusters display extraordinarily diverse organizations, and a total of 1,147 hybrid NRPS/PKS clusters were found. Surprisingly, 10% of bacterial gene clusters lacked modular organization, and instead catalytic domains were mostly encoded as separate proteins. The finding of common occurrence of nonmodular NRPS differs substantially from the current classification. Sequence analysis indicates that the evolution of NRPS machineries was driven by a combination of common descent and horizontal gene transfer. We identified related siderophore NRPS gene clusters that encoded modular and nonmodular NRPS enzymes organized in a gradient. A higher frequency of the NRPS and PKS gene clusters was detected from bacteria compared with archaea or eukarya. They commonly occurred in the phyla of Proteobacteria, Actinobacteria, Firmicutes, and Cyanobacteria in bacteria and the phylum of Ascomycota in fungi. The majority of these NRPS and PKS gene clusters have unknown end products highlighting the power of genome mining in identifying novel genetic machinery for the biosynthesis of secondary metabolites.biosynthetic gene cluster | data mining | distribution | bioactive compound

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Section: Discussionmentioning

confidence: 99%

Atlas of nonribosomal peptide and polyketide biosynthetic pathways reveals common occurrence of nonmodular enzymes

Wang¹,

Fewer²,

Holm

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

293

263

View full text Add to dashboard Cite

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“…With sizes of 8.54, 8.7 and 9.03 Mb, the genomes of S. griseus, S. coelicolor and Streptomyces avermitilis, respectively, are among the largest genomes found in the microbial world. 70,71 Moreover, streptomycetes have higher GC content (470%) than nearly all other organisms. Unlike most other eubacterial chromosomes, the chromosome of this genus is linear with terminal-inverted repeats and covalently bound terminal proteins at the 5¢ end.…”

Section: Streptomycesmentioning

confidence: 99%

Carbon source regulation of antibiotic production

et al. 2010

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“…Members of the Actinobacteria are encountered in a wide range of ecosystems, from soil and seawater to the skin, lungs, and gastrointestinal tract of humans, and are responsible for the production of commercial products, including amino acids, vitamins, and antibiotics (52,155), as well as for causing important human diseases, such as leprosy, tuberculosis, and diphtheria. In addition, members of the Actinobacteria are used in the biodegradation of organic compounds during bioremediation (62).…”

Section: Introductionmentioning

confidence: 99%

Biosynthesis and Functions of Mycothiol, the Unique Protective Thiol of Actinobacteria

Newton

Buchmeier

Fahey

2008

Microbiol Mol Biol Rev

313

293

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SUMMARY Mycothiol (MSH; AcCys-GlcN-Ins) is the major thiol found in Actinobacteria and has many of the functions of glutathione, which is the dominant thiol in other bacteria and eukaryotes but is absent in Actinobacteria. MSH functions as a protected reserve of cysteine and in the detoxification of alkylating agents, reactive oxygen and nitrogen species, and antibiotics. MSH also acts as a thiol buffer which is important in maintaining the highly reducing environment within the cell and protecting against disulfide stress. The pathway of MSH biosynthesis involves production of GlcNAc-Ins-P by MSH glycosyltransferase (MshA), dephosphorylation by the MSH phosphatase MshA2 (not yet identified), deacetylation by MshB to produce GlcN-Ins, linkage to Cys by the MSH ligase MshC, and acetylation by MSH synthase (MshD), yielding MSH. Studies of MSH mutants have shown that the MSH glycosyltransferase MshA and the MSH ligase MshC are required for MSH production, whereas mutants in the MSH deacetylase MshB and the acetyltransferase (MSH synthase) MshD produce some MSH and/or a closely related thiol. Current evidence indicates that MSH biosynthesis is controlled by transcriptional regulation mediated by σB and σR in Streptomyces coelicolor. Identified enzymes of MSH metabolism include mycothione reductase (disulfide reductase; Mtr), the S-nitrosomycothiol reductase MscR, the MSH S-conjugate amidase Mca, and an MSH-dependent maleylpyruvate isomerase. Mca cleaves MSH S-conjugates to generate mercapturic acids (AcCySR), excreted from the cell, and GlcN-Ins, used for resynthesis of MSH. The phenotypes of MSH-deficient mutants indicate the occurrence of one or more MSH-dependent S-transferases, peroxidases, and mycoredoxins, which are important targets for future studies. Current evidence suggests that several MSH biosynthetic and metabolic enzymes are potential targets for drugs against tuberculosis. The functions of MSH in antibiotic-producing streptomycetes and in bioremediation are areas for future study.

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Exploiting the genetic potential of polyketide producing streptomycetes

Cited by 131 publications

References 76 publications

Atlas of nonribosomal peptide and polyketide biosynthetic pathways reveals common occurrence of nonmodular enzymes

Atlas of nonribosomal peptide and polyketide biosynthetic pathways reveals common occurrence of nonmodular enzymes

Carbon source regulation of antibiotic production

Biosynthesis and Functions of Mycothiol, the Unique Protective Thiol of Actinobacteria

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