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Inactivation of the ketoreductase gilU gene of the gilvocarcin biosynthetic gene cluster yields new analogues with partly improved biological activity.

ABSTRACT: Four new analogues of the gilvocarcin-type aryl-C-glycoside antitumor compounds, namely 4'-hydroxy gilvocarcin V (4'-OH-GV), 4'-hydroxy gilvocarcin M, 4'-hydroxy gilvocarcin E and 12-demethyl-defucogilvocarcin V, were produced through inactivation of the gilU gene. The 4'-OH-analogues showed improved activity against lung cancer cell lines as compared to their parent compounds without 4'-OH group (gilvocarcins V and E). The structures of the sugar-containing new mutant products indicate that the enzyme GilU acts as an unusual ketoreductase involved in the biosynthesis of the C-glycosidically linked deoxysugar moiety of the gilvocarcins. The structures of the new gilvocarcins indicate substrate flexibility of the post-polyketide synthase modifying enzymes, particularly the C-glycosyltransferase and the enzyme responsible for the sugar ring contraction. The results also shed light into biosynthetic sequence of events in the late steps of biosynthetic pathway of gilvocarcin V.

SUBMITTER: Liu T

PROVIDER: S-EPMC2680003 | biostudies-literature | 2009 Jan

REPOSITORIES: biostudies-literature

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Inactivation of the ketoreductase gilU gene of the gilvocarcin biosynthetic gene cluster yields new analogues with partly improved biological activity.

Liu Tao T Kharel Madan K MK Zhu Lili L Bright Samuel A SA Mattingly Cynthia C Adams Val R VR Rohr Jürgen J

Chembiochem : a European journal of chemical biology 20090101 2

Four new analogues of the gilvocarcin-type aryl-C-glycoside antitumor compounds, namely 4'-hydroxy gilvocarcin V (4'-OH-GV), 4'-hydroxy gilvocarcin M, 4'-hydroxy gilvocarcin E and 12-demethyl-defucogilvocarcin V, were produced through inactivation of the gilU gene. The 4'-OH-analogues showed improved activity against lung cancer cell lines as compared to their parent compounds without 4'-OH group (gilvocarcins V and E). The structures of the sugar-containing new mutant products indicate that the ...[more]

PMID: 19067453

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Project description:Streptomyces scabies is a phytopathogen associated with common scab disease. This is mainly attributed to its ability to produce the phytotoxin thaxtomin A, the biosynthesis of which is triggered by cellobiose. During a survey of other metabolites released in the presence of cellobiose, we discovered additional compounds in the thaxtomin-containing extract from Streptomyces scabies. Structural analysis by mass spectrometry (MS) and nuclear magnetic resonance (NMR) revealed that these compounds are amino acid sequence variants of the TOR (target of rapamycin) kinase (TORK) pathway-inhibitory lipopeptide rotihibin A, and the main compounds were named rotihibins C and D. In contrast to thaxtomin, the production of rotihibins C and D was also elicited in the presence of glucose, indicating different regulation of their biosynthesis. Through a combination of shotgun and targeted proteomics, the putative rotihibin biosynthetic gene cluster rth was identified in the publicly available genome of S. scabies 87-22. This cluster spans 33 kbp and encodes 2 different nonribosomal peptide synthetases (NRPSs) and 12 additional enzymes. Homologous rth biosynthetic gene clusters were found in other publicly available and complete actinomycete genomes. Rotihibins C and D display herbicidal activity against Lemna minor and Arabidopsis thaliana at low concentrations, shown by monitoring the effects on growth and the maximal photochemistry efficiency of photosystem II. IMPORTANCE Rotihibins A and B are plant growth inhibitors acting on the TORK pathway. We report the isolation and characterization of new sequence analogues of rotihibin from Streptomyces scabies, a major cause of common scab in potato and other tuber and root vegetables. By combining proteomics data with genomic analysis, we found a cryptic biosynthetic gene cluster coding for enzyme machinery capable of rotihibin production. This work may lead to the biotechnological production of variants of this lipopeptide to investigate the exact mechanism by which it can target the plant TORK pathway in Arabidopsis thaliana. In addition, bioinformatics revealed the existence of other variants in plant-associated Streptomyces strains, both pathogenic and nonpathogenic species, raising new questions about the actual function of this lipopeptide. The discovery of a module in the nonribosomal peptide synthetase (NRPS) that incorporates the unusual citrulline residue may improve the prediction of peptides encoded by cryptic NRPS gene clusters.

Dataset Information

Inactivation of the ketoreductase gilU gene of the gilvocarcin biosynthetic gene cluster yields new analogues with partly improved biological activity.

Publications

Inactivation of the ketoreductase gilU gene of the gilvocarcin biosynthetic gene cluster yields new analogues with partly improved biological activity.

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