Manipulation of polyketide biosynthesis for new drug discovery.
Modular polyketide synthases (PKS) are large multifunctional proteins which direct the condensation of activated short chain carboxylic acids into products of defined length and functionality using a dedicated set of active sites, or module, for each step in the polymerization. The structure of the product is directly related to the number, content and sequence of modules in a PKS. Technology is described which allows the rational manipulation of the biosynthesis of these compounds and enables the generation of specific novel polyketide structures. Examples of polyketide drugs whose structures may be manipulated using this technology are given.
Carreras
C W
CW
Department of New Technologies, Kosan Biosciences, Inc., Hayward, CA 94545, USA.
Ashley
G W
GW
D000818:Animals; D000900:Anti-Bacterial Agents / Q000096:biosynthesis* / Q000737:chemistry; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis / Q000737:chemistry; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry; D000977:Antiparasitic Agents / Q000138:chemical synthesis / Q000737:chemistry; D020650:Combinatorial Chemistry Techniques; D015195:Drug Design; D006801:Humans; D007166:Immunosuppressive Agents / Q000138:chemical synthesis / Q000737:chemistry; D018942:Macrolides; D046911:Macromolecular Substances; D009097:Multienzyme Complexes / Q000737:chemistry / Q000378:metabolism*; D009414:Nerve Growth Factors / Q000138:chemical synthesis / Q000737:chemistry; D010084:Oxidation-Reduction; D013237:Stereoisomerism
D000900:Anti-Bacterial Agents; D000894:Anti-Inflammatory Agents, Non-Steroidal; D000970:Antineoplastic Agents; D000977:Antiparasitic Agents; D007166:Immunosuppressive Agents; D018942:Macrolides; D046911:Macromolecular Substances; D009097:Multienzyme Complexes; D009414:Nerve Growth Factors