A tylosin ketoreductase reveals how chirality is determined in polyketides.
Because it controls the majority of polyketide stereocenters, the ketoreductase (KR) is a central target in engineering polyketide synthases (PKSs). To elucidate the mechanisms of stereocontrol, the structure of KR from the first module of the tylosin PKS was determined. A comparison with a recently solved erythromycin KR that operates on the same substrate explains why their products have opposite alpha-substituent chiralities. The structure reveals how polyketides are guided into the active site by key residues in different KR types. There are four types of reductase-competent KRs, each capable of fixing a unique combination of alpha-substituent and beta-hydroxyl group chiralities, as well as two types of reductase-incompetent KRs that control alpha-substituent chirality alone. A protocol to assign how a module will enforce substituent chirality based on its sequence is presented.
Keatinge-Clay
Adrian T
AT
Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA 94158, USA. adriankc@msg.ucsf.edu
D000429:Alcohol Oxidoreductases / Q000737:chemistry* / Q000235:genetics; D000595:Amino Acid Sequence; D001483:Base Sequence; D001665:Binding Sites; D003001:Cloning, Molecular; D017931:DNA Primers; D018942:Macrolides / Q000737:chemistry*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D015202:Protein Engineering; D017386:Sequence Homology, Amino Acid; D013237:Stereoisomerism
D017931:DNA Primers; D018942:Macrolides; D000429:Alcohol Oxidoreductases; C082907:tylosin reductase