Structural highlights
Publication Abstract from PubMedThe process by which alpha-stereocenters of polyketide intermediates are set by modular polyketide synthases (PKSs) when condensation is not immediately followed by reduction is mysterious. However, the reductase-incompetent ketoreductase (KR) from the third module of 6-deoxyerythronolide B synthase has been proposed to operate as a racemase, aiding in the epimerization process that reverses the orientation of the alpha-methyl group of the polyketide intermediate generated by the ketosynthase to the configuration observed in the 6-deoxyerythronolide B final product. To learn more about the epimerization process, the structure of the C2-type KR from the third module of the pikromycin synthase, analogous to the KR from the third module of 6-deoxyerythronolide B synthase, was determined to 1.88 A resolution. This first structural analysis of this KR-type reveals differences from reductase-competent KRs such as that the site NADPH binds to reductase-competent KRs is occluded by side chains and the putative catalytic tyrosine possesses more degrees of freedom. The active-site geometry may enable C2-type KRs to align the thioester and beta-keto groups of a polyketide intermediate to reduce the pK(a) of the alpha-proton and accelerate its abstraction. Results from in vivo assays of engineered PKSs support that C2-type KRs cooperate with epimer-specific ketosynthases to set the configurations of substituent-bearing alpha-carbons. Structural and functional analysis of c2-type ketoreductases from modular polyketide synthases.,Zheng J, Keatinge-Clay AT J Mol Biol. 2011 Jul 1;410(1):105-17. Epub 2011 May 5. PMID:21570406[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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