3QP9

The Structure of a C2-type Ketoreductase from a Modular Polyketide Synthase

Summary for 3QP9

• Entry DOI: 10.2210/pdb3qp9/pdb
• Descriptor: Type I polyketide synthase PikAII (2 entities in total)
• Functional Keywords: rossmann fold, ketoreductase, epimerization, oxidoreductase
• Biological source: Streptomyces venezuelae
• Total number of polymer chains: 4
• Total formula weight: 214018.22

Authors

Zheng, J.,Keatinge-Clay, A.T. (deposition date: 2011-02-11, release date: 2011-05-11, Last modification date: 2023-09-13)

Primary citation

Zheng, J.,Keatinge-Clay, A.T.
Structural and functional analysis of c2-type ketoreductases from modular polyketide synthases.
J.Mol.Biol., 410:105-117, 2011

PubMed Abstract: The process by which α-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 α-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 Å 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 β-keto groups of a polyketide intermediate to reduce the pK(a) of the α-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 α-carbons.

PubMed: 21570406
DOI: 10.1016/j.jmb.2011.04.065

Experimental method

X-RAY DIFFRACTION (1.88 Å)