Employing modular polyketide synthase ketoreductases as biocatalysts in the preparative chemoenzymatic syntheses of diketide chiral building blocks.
Chiral building blocks are valuable intermediates in the syntheses of natural products and pharmaceuticals. A scalable chemoenzymatic route to chiral diketides has been developed that includes the general synthesis of α-substituted, β-ketoacyl N-acetylcysteamine thioesters followed by a biocatalytic cycle in which a glucose-fueled NADPH-regeneration system drives reductions catalyzed by isolated modular polyketide synthase (PKS) ketoreductases (KRs). To identify KRs that operate as active, stereospecific biocatalysts, 11 isolated KRs were incubated with 5 diketides and their products were analyzed by chiral chromatography. KRs that naturally reduce small polyketide intermediates were the most active and stereospecific toward the panel of diketides. Several biocatalytic reactions were scaled up to yield more than 100 mg of product. These syntheses demonstrate the ability of PKS enzymes to economically and greenly generate diverse chiral building blocks on a preparative scale.
Institute for Cellular and Molecular Biology, The University of Texas at Austin, Austin, TX 78712, USA.
Shawn K
SK
Piasecki
Clint A
CA
Taylor
Joshua F
JF
Detelich
June
J
Liu
Jianting
J
Zheng
Arkady
A
Komsoukaniants
Dionicio R
DR
Siegel
Adrian T
AT
Keatinge-Clay
D000429:Alcohol Oxidoreductases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D001426:Bacterial Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D001709:Biotechnology / Q000379:methods; D002384:Catalysis; D003543:Cysteamine / Q000031:analogs & derivatives / Q000737:chemistry; D009249:NADP / Q000378:metabolism; D048630:Polyketide Synthases / Q000737:chemistry / Q000378:metabolism; D061065:Polyketides / Q000138:chemical synthesis*; D013237:Stereoisomerism
D001426:Bacterial Proteins; D061065:Polyketides; D009249:NADP; D003543:Cysteamine; D048630:Polyketide Synthases; D000429:Alcohol Oxidoreductases; C087192:polyketide synthase ketoreductase