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Biosynthetic studies of the cyclocarbamate SB-253514
Lipoprotein associated phospholipase A2 (LpPLA2) is responsible for hydrolysis of modified oxidized phospholipids from low density lipoprotein causing the release of pro-inflammatory lyso-phosphatidyl choline and oxidatively modified fatty acids. Inhibition of LpPLA2 is therefore considered a novel therapeutic strategy in the treatment of diseases that have an inflammatory component such as atherosclerosis. One of these metabolites is SB-253514, a glycosylated lipopeptide produced by Pseudomonas fluorescens . The structure consists of a 5,5-bicyclic carbamate moiety, connected via two carbons and one nitrogen atom to myristic acid, which is in turn glycosylated with rhamnose. During a genomic-driven screening for lipopeptide gene clusters, we recently came across the corresponding gene cluster of SB-253514 which involves unexpectedly a two modular NRPS gene cluster. Both, its unique structure and its powerful Lp-PLA2-inhibition prompted our study of its biosynthesis. Of particular interest is hereby the modification of the putative involved second amino acid aside proline and the formation of the cyclocarbamate structure. This poster will describe our recent efforts to elucidate the biosynthesis using knockout strains as well as stable isotope feeding experiments.
Acknowledgements: Financial support by the German Research Foundation (DFG FOR 854) is gratefully acknowledged.
References: 1. Pinto et al. (2000) Bioorg. Med. Chem. Letters 10:2015–2017.