title: 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.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, 725 Rose Street, Lexington, KY 40536-0082, USA.
authors.forename: Tao
authors.initials: T
authors.lastname: Liu
authors.forename: Madan K
authors.initials: MK
authors.lastname: Kharel
authors.forename: Lili
authors.initials: L
authors.lastname: Zhu
authors.forename: Samuel A
authors.initials: SA
authors.lastname: Bright
authors.forename: Cynthia
authors.initials: C
authors.lastname: Mattingly
authors.forename: Val R
authors.initials: VR
authors.lastname: Adams
authors.forename: Jürgen
authors.initials: J
authors.lastname: Rohr
mesh_terms: D000429:Alcohol Oxidoreductases / Q000235:genetics*; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003374:Coumarins / Q000737:chemistry / Q000494:pharmacology*; D004926:Escherichia coli / Q000235:genetics* / Q000378:metabolism; D017353:Gene Deletion; D020868:Gene Silencing; D006027:Glycosides / Q000096:biosynthesis* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D005810:Multigene Family / Q000235:genetics*; D048170:Streptomyces lividans / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D003374:Coumarins; D006027:Glycosides; C031781:gilvocarcin V; D000429:Alcohol Oxidoreductases