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Inactivation of the Ketoreductase gilU Gene of the Gilvocarcin Biosynthetic Gene Cluster Yields New Analogues with Partly Improved Biological Activity
Author(s) -
Liu Tao,
Kharel Madan K.,
Zhu Lili,
Bright Samuel A.,
Mattingly Cynthia,
Adams Val R.,
Rohr Jürgen
Publication year - 2009
Publication title -
chembiochem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.05
H-Index - 126
eISSN - 1439-7633
pISSN - 1439-4227
DOI - 10.1002/cbic.200800348
Subject(s) - gene cluster , gene , chemistry , biology , biochemistry , genetics , computational biology
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.