Poliketides

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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: js24@cam.ac.uk or kjw21@cus.cam.ac.uk 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 biosynthetichypothesis 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 Organisationand 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 proteins9 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 processingGenetic 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 Geneticstudies on the type II PKS systems Studies in vitro of type II PKSs Summary of the advancements in the understanding of type II polyketide biosynthesis

Jim Staunton graduated from Liverpool University in 1959 with a PhD based on elucidation of the structures of the fungal metabolites, sclerotiorin and rotiorin. After a postdoctoral fellowship in Carl Djerassi’s group at Stanford, California, hereturned to the UK to take up a lectureship post at Liverpool University. In 1969, following a move to a similar post in Cambridge, he began his research into polyketide biosynthesis. Although he was primarily interested in the elucidation of biosynthetic pathways, he has made important contributions to biomimetic synthesis and enantiospecific synthesis in this field. He also developed noveltechnologies for tracing stable isotopes which had a strong influence on the development of biosynthetic studies. In recent years he has collaborated with Professor Peter Leadlay in running a multidisciplinary group of chemists and biologists dedicated to biosynthetic studies of complex polyketides.

Kira Weissman was born in Stanford, CA in 1973. She studied chemistry at Stanford University, CA,obtaining a BS in 1995. She then moved to the University of Cambridge, UK where she obtained both her MPhil (1996) and PhD (1999) in chemistry under the guidance of Professor James Staunton. Her doctoral research concerned various aspects of erythromycin biosynthesis, particularly the mechanism of stereocontrol. Kira is continuing her research on aliphatic polyketides as a Junior Research Fellow atNewnham College, working in the lab of Professor Peter Leadlay.

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Nat. Prod. Rep., 2001, 18, 380–416 This journal is © The Royal Society of Chemistry 2001

DOI: 10.1039/a909079g

15 15.1 15.2 16 17 1

Biosynthesis of plant polyketides Structural studies of the chalcone synthases Bacterial analogues of CHSs Conclusions References

Introduction

The polyketide natural products (Fig....
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