Poliketides

MILLENNIUM REVIEW

Polyketide biosynthesis: a millennium review
James Staunton and Kira J. Weissman Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW. E-mail: [e-mail] or [e-mail] Received (in Cambridge, UK) 13th March 2001 First published as an Advance Article on the web 4th June 2001
1 2 2.1 3 Introduction Development of the biosynthetic hypothesis The polyketide field is revived The application of isotopic labelling to studying biosynthesis 4 Biomimetic syntheses of aromatic polyketides 5 Enzymology of fatty acid and polyketide biosynthesis 5.1 Fatty acid biosynthesis 6 The genetic approach to biosynthetic studies 6.1 Genetics of type I or modular polyketide synthases 6.1.1 The erythromycin polyketide synthase 6.1.1.1 Organisation and function of the erythromycin PKS 6.2 Other type I modular PKSs 7 Type I iterative modular polyketide synthases 7.1 6-Methylsalicylic acid synthase 7.2 Lovastatin polyketide synthases 8 Structural studies on the type I modular polyketide synthases 8.1 Experiments to probe the structure of the erythromycin PKS 8.2 Proposed structural models for the erythromycin PKS 8.3 Docking of modular proteins 9 9.1 9.2 9.3 9.3.1 9.3.2 9.3.3 9.3.4 9.3.5 10 11 11.1 11.2 11.3 11.4 11.5 11.5.1 12 13 14 Genetics engineering of type I modular polyketide synthases Polyketides as targets for ‘combinatorial biochemistry’ Expression of polyketide synthases Genetic engineering strategies Domain mutagenesis Linking of modules Combining protein subunits Mutational biosynthesis (mutasynthesis) Post-PKS processing Genetic engineering of type I iterative polyketide synthases Mechanistic studies in vitro on type I modular polyketide synthases Studies in vitro with the DEBS PKS Model systems for studying erythromycin biosynthesis: DEBS 1-TE and DEBS 1 TE Substrate specificity of DEBS 1 The molecular basis of stereocontrol Studies in vitro of the erythromycin thioesterase Substrate specificity of the TE Genetic