title: Alteration of Polyketide Stereochemistry from anti to syn by a Ketoreductase Domain Exchange in a Type I Modular Polyketide Synthase Subunit.
abstract: Polyketide natural products have broad applications in medicine. Exploiting the modular nature of polyketide synthases to alter stereospecificity is an attractive strategy for obtaining natural product analogues with altered pharmaceutical properties. We demonstrate that by retaining a dimerization element present in LipPks1+TE, we are able to use a ketoreductase domain exchange to alter α-methyl group stereochemistry with unprecedented retention of activity and simultaneously achieve a novel alteration of polyketide product stereochemistry from anti to syn. The substrate promiscuity of LipPks1+TE further provided a unique opportunity to investigate the substrate dependence of ketoreductase activity in a polyketide synthase module context.
authors.affiliation: Synthetic Biology Engineering Research Center , 5885 Hollis Street, Emeryville, California 94608, United States.
authors.forename: Clara H
authors.initials: CH
authors.lastname: Eng
authors.forename: Satoshi
authors.initials: S
authors.lastname: Yuzawa
authors.affiliation: Joint BioEnergy Institute , 5885 Hollis Street, Emeryville, California 94608, United States.|Biological Systems and Engineering Division, Lawrence Berkeley National Laboratory , Berkeley, California 94270, United States.
authors.forename: George
authors.initials: G
authors.lastname: Wang
authors.affiliation: Joint BioEnergy Institute , 5885 Hollis Street, Emeryville, California 94608, United States.|Biological Systems and Engineering Division, Lawrence Berkeley National Laboratory , Berkeley, California 94270, United States.
authors.forename: Edward E K
authors.initials: EE
authors.lastname: Baidoo
authors.affiliation: Synthetic Biology Engineering Research Center , 5885 Hollis Street, Emeryville, California 94608, United States.
authors.forename: Leonard
authors.initials: L
authors.lastname: Katz
authors.affiliation: Synthetic Biology Engineering Research Center , 5885 Hollis Street, Emeryville, California 94608, United States.|Joint BioEnergy Institute , 5885 Hollis Street, Emeryville, California 94608, United States.|Biological Systems and Engineering Division, Lawrence Berkeley National Laboratory , Berkeley, California 94270, United States.
authors.forename: Jay D
authors.initials: JD
authors.lastname: Keasling
mesh_terms: D001426:Bacterial Proteins / Q000737:chemistry* / Q000378:metabolism; D048630:Polyketide Synthases / Q000737:chemistry* / Q000378:metabolism; D017434:Protein Structure, Tertiary / Q000502:physiology; D021122:Protein Subunits / Q000737:chemistry* / Q000378:metabolism; D013237:Stereoisomerism; D013304:Streptomyces aureofaciens / Q000201:enzymology
chemical_list: D001426:Bacterial Proteins; D021122:Protein Subunits; D048630:Polyketide Synthases