Engineering of complex polyketide biosynthesis - insights from sequencing of the monensin biosynthetic gene cluster

Leadlay, P.F., Staunton, J., Oliynyk, M., Bisang, C.P., Cortes, J., Frost, E., Hughes-Thomas, Z.A., Jones, M.A., Kendrew, S.G., Lester, J.B., Long, P.F., McArthur, H.A., McCormick, E.L., Oliynyk, Z., Stark, C.B.W. and Wilkinson, C.J. (2001) Engineering of complex polyketide biosynthesis - insights from sequencing of the monensin biosynthetic gene cluster. Journal of Industrial Microbiology and Biotechnology, 27 (6). p. 360. 10.1038/sj.jim.7000204.

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DOI: 10.1038/sj.jim.7000204

Abstract

The biosynthesis of complex reduced polyketides is catalysed in actinomycetes by large multifunctional enzymes, the modular rfetiType I polyketide synthases (PKSs). Most of our current knowledge of such systems stems from the study of a restricted number of macrolide-synthesising enzymes. The sequencing of the genes for the biosynthesis of monensin A, a typical polyether ionophore polyketide, provided the first genetic evidence for the mechanism of oxidative cyclisation through which polyethers such as monensin are formed from the uncyclised products of the PKS. Two intriguing genes associated with the monensin PKS cluster code for proteins, which show strong homology with enzymes that trigger double bond migrations in steroid biosynthesis by generation of an extended enolate of an unsaturated ketone residue. A similar mechanism operating at the stage of an enoyl ester intermediate during chain extension on a PKS could allow isomerisation of an E double bond to the Z isomer. This process, together with epoxidations and cyclisations, form the basis of a revised proposal for monensin formation. The monensin PKS has also provided fresh insight into general features of catalysis by modular PKSs, in particular into the mechanism of chain initiation.

Item Type:Article
Uncontrolled Keywords:Antibiotic biosynthesis; Monensin; Polyether; Polyketide synthase
Departments, units and centres:Department of Pharmaceutics > Department of Pharmaceutics
ID Code:3226
Journal or Publication Title:Journal of Industrial Microbiology and Biotechnology
Deposited By:Library Staff
Deposited On:17 May 2012 12:27
Last Modified:17 May 2012 12:54

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