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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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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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