Harnessing the Biosynthetic Code: Combinations, Permutations, and Mutations-Reference-Cited by-同舟云学术

Harnessing the Biosynthetic Code: Combinations, Permutations, and Mutations

Published:1998-10-02 Issue:5386 Volume:282 Page:63-68
ISSN:0036-8075
Container-title:Science
language:en
Short-container-title:Science

Author:

Cane David E.¹,Walsh Christopher T.¹,Khosla Chaitan¹

Affiliation:

1. 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.

Abstract

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.

Publisher

American Association for the Advancement of Science (AAAS)

Subject

Multidisciplinary

Reference72 articles.

1. For a thematic issue reviewing the recent literature on the molecular genetics and enzymology of polyketide and non-ribosomal peptide biosynthesis see Chem. Rev. 97 (November 1997).

2. It has often been argued that the observed biological potency and selectivity of these microbial metabolites is the result of evolutionary pressures. While this simple argument may be true for some natural products an increasing number of examples suggest that the complete picture is far more complex. For example erythromycin A an antibiotic produced by the soil organism Saccharopolyspora erythraea and which inhibits ribosomal protein biosynthesis in bacteria readily undergoes an intramolecular cyclization under acidic conditions such as found in the stomach so as to generate a rearranged metabolite that is inactive as an antibacterial but is now a potent agonist of the motilin receptor [

3. Omura S., et al., J. Med. Chem. 30, 1943 (1987);

4. Lartey P. A., et al., ibid. 38, 1793 (1995);

5. ]. Clearly these two properties associated with the same fundamental natural product skeleton are mechanistically unrelated and it is unlikely that evolutionary pressures led to the simultaneous optimization of both properties. What is undisputed about these families of natural products are their intrinsic pharmacological properties.

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