Document Detail


Bacterial biosynthetic gene clusters encoding the anti-cancer haterumalide class of molecules: biogenesis of the broad spectrum antifungal and anti-oomycete compound, oocydin A.
MedLine Citation:
PMID:  23012376     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Haterumalides are halogenated macrolides with strong antitumor properties, making them attractive targets for chemical synthesis. Unfortunately, current synthetic routes to these molecules are inefficient. The potent haterumalide, oocydin A, was previously identified from two plant-associated bacteria through its high bioactivity against plant pathogenic fungi and oomycetes. In this study, we describe oocydin A (ooc) biosynthetic gene clusters identified by genome sequencing, comparative genomics, and chemical analysis in four plant-associated enterobacteria of the Serratia and Dickeya genera. Disruption of the ooc gene cluster abolished oocydin A production and bioactivity against fungi and oomycetes. The ooc gene clusters span between 77 and 80 kb and encode five multimodular polyketide synthase (PKS) proteins, a hydroxymethylglutaryl-CoA synthase cassette and three flavin-dependent tailoring enzymes. The presence of two free-standing acyltransferase proteins classifies the oocydin A gene cluster within the growing family of trans-AT PKSs. The amino acid sequences and organization of the PKS domains are consistent with the chemical predictions and functional peculiarities associated with trans-acyltransferase PKS. Based on extensive in silico analysis of the gene cluster, we propose a biosynthetic model for the production of oocydin A and, by extension, for other members of the haterumalide family of halogenated macrolides exhibiting anti-cancer, anti-fungal, and other interesting biological properties.
Authors:
Miguel A Matilla; Henning Stöckmann; Finian J Leeper; George P C Salmond
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2012-09-24
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  287     ISSN:  1083-351X     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2012 Nov 
Date Detail:
Created Date:  2012-11-12     Completed Date:  2013-01-31     Revised Date:  2013-11-14    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  39125-38     Citation Subset:  IM    
Affiliation:
Department of Biochemistry, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QW, United Kingdom.
Data Bank Information
Bank Name/Acc. No.:
GENBANK/JX315603;  JX315604
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MeSH Terms
Descriptor/Qualifier:
Animals
Antifungal Agents / pharmacology
Antineoplastic Agents / pharmacology*
Biofilms
Caenorhabditis elegans
Chromatography, Liquid / methods
Genome
Lactones / pharmacology
Macrolides / metabolism,  pharmacology*
Mass Spectrometry / methods
Models, Genetic
Molecular Conformation
Molecular Sequence Data
Multigene Family*
Mutagenesis
Oomycetes / metabolism*
Plasmids / metabolism
Polyketide Synthases / genetics
Polyketides / chemistry
Transcription, Genetic
Chemical
Reg. No./Substance:
0/Antifungal Agents; 0/Antineoplastic Agents; 0/Lactones; 0/Macrolides; 0/Polyketides; 0/haterumalide NA; 0/oocydin A; 79956-01-7/Polyketide Synthases
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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