Type I Modular PKS

Polyketides (PKs) are secondary metabolites produced by bacteria, fungi, and plants. Many of these metabolites have important biological activity and have found clinical use as antibiotics, antifungals, anticancer drugs, and immunosuppressants. In this chapter, we discuss the modular type I polyketide synthases (PKSs) using the 6-deoxyerythronolide B synthase (DEBS) to illustrate reactions and enzymes used in PK synthesis, and the protein–protein interactions that are required for this process. A detailed discussion of the quaternary structure of PKSs is given, including evidence from both solution and structural studies, and from intact synthases and isolated domains. Other PKSs are discussed to show different strategies for chain initiation, extension, and termination. The importance of reaction kinetics for control of fidelity in product formation is discussed, and two alternative effects, residence-time control and occupancy-level control, are introduced. Some commercial applications of genetic manipulation of modular PKSs are also discussed.