Accumulation of anE,E,E-Triene by the Monensin-Producing Polyketide Synthase when Oxidative Cyclization is Blocked (original) (raw)
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Journal of Industrial Microbiology & Biotechnology, 2001
The biosynthesis of complex reduced polyketides is catalysed in actinomycetes by large multifunctional enzymes, the modular Type 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. Journal of Industrial Microbiology & Biotechnology (2001) 27, 360–367.
Evidence for the Role of the monB Genes in Polyether Ring Formation during Monensin Biosynthesis
Chemistry & Biology, 2006
Ionophoric polyethers are produced by the exquisitely stereoselective oxidative cyclization of a linear polyketide, probably via a triepoxide intermediate. We report here that deletion of either or both of the monBI and monBII genes from the monensin biosynthetic gene cluster gave strains that produced, in place of monensins A and B, a mixture of C-3-demethylmonensins and a number of minor components, including C-9-epimonensin A. All the minor components were efficiently converted into monensins by subsequent acid treatment. These data strongly suggest that epoxide ring opening and concomitant polyether ring formation are catalyzed by the MonB enzymes, rather than by the enzyme MonCII as previously thought. Consistent with this, homology modeling shows that the structure of MonB-type enzymes closely resembles the recently determined structure of limonene-1,2-epoxide hydrolase from Rhodococcus erythropolis.
Polyether biosynthesis. 2. Origin of the oxygen atoms of monensin A
Journal of The American Chemical Society, 1982
Feeding of [l-I3C]acetate to cultures of Streptomyces cinnamonensis gave monensin A labeled at carbons 7, 9, 13, 19, and 25, as established by 13C N M R analysis. Similarly, incorporation of [l-13C]propionate resulted in enrichment of carbons 1, 3, 5 , 11, 17, 21, and 23. Further incorporations of [ 1,2-I3C2]acetate, [1,2-13C2]propionate, [2-13C]propionate,
New Start and Finish for Complex Polyketide Biosynthesis
Chemistry & Biology, 2004
as well as a loading module for transferring the starter acyl group onto the first KS domain. This modular orga-Biosynthesis nization allows programmed assembly of a defined sequence of starter and extender units, together with controlled processing of each -ketone group. The final The polyketide vicenistatin has significant anticancer product may be cyclized by a thioesterase (TE) to give activity. In the January issue of Chemistry & Biology, a macrolactone.
ChemInform Abstract: Biosynthesis of Polyketide Synthase Extender Units
ChemInform, 2009
The biosynthetic pathways to polyketide-derived polycyclic ethers, in bacteria, plants and marine organisms, have, until now, tended to be considered separately. The purpose of this article is to provide an integrated review of the common mechanistic aspects of polyether biosynthesis from these diverse sources. In particular, the focus will be on the proposed mechanisms of oxidative cyclisation, as well as on the known differences in polyketide chain construction between the terrestrial and marine polyethers.