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Science 2 October 1998:
Vol. 282. no. 5386, pp. 63 - 68
DOI: 10.1126/science.282.5386.63
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Review

Harnessing the Biosynthetic Code: Combinations, Permutations, and Mutations

David E. Cane, Christopher T. Walsh, Chaitan Khosla *

Polyketides and non-ribosomal peptides are two large families of complex natural products that are built from simple carboxylic acid or amino acid monomers, respectively, and that have important medicinal or agrochemical properties. Despite the substantial differences between these two classes of natural products, each is synthesized biologically under the control of exceptionally large, multifunctional proteins termed polyketide synthases (PKSs) and non-ribosomal peptide synthetases (NRPSs) that contain repeated, coordinated groups of active sites called modules, in which each module is responsible for catalysis of one complete cycle of polyketide or polypeptide chain elongation and associated functional group modifications. It has recently become possible to use molecular genetic methodology to alter the number, content, and order of such modules and, in so doing, to alter rationally the structure of the resultant products. This review considers the promise and challenges inherent in the combinatorial manipulation of PKS and NRPS structure in order to generate entirely "unnatural" products.

D. E. Cane, Department of Chemistry, Box H, Brown University, Providence, RI 02912-9108, USA. C. T. Walsh, Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA. C. Khosla, Departments of Chemical Engineering, Chemistry, and Biochemistry, Stanford University, Stanford, CA 94305-5025, USA.
*   On sabbatical at Kosan Biosciences, Burlingame, CA 94010, USA.

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