Comprehensive Analysis of Polyketide Synthase Families

Polyketides (PKs) are a class of natural products (secondary metabolites) from bacteria, fungi, and plants, including many clinically important drugs such as tetracycline, daunorubicin, erythromycin, rapamycin and lovastatin [1, 4]. They have a large diversity of biological activities and pharmacological properties such as antibiotic, anticancer, antifungal, antiparasitic, cytostatic, and immunosuppressive properties. They are biosynthesized by the sequential condensation of two-carbon acetate units derived from malonate thioester in a similar process to fatty acid synthesis. The individual chain elongation intermediates of polyketide biosynthesis undergo all, some, or none of functional group modifications. This is the reason why products (PKs) have the large complexity. These reactions are catalyzed by polyketide synthases (PKSs), which are classified into 3 types: type I, type II, and type III [1, 3, 4]. PKS protein consists of some modules for the corresponding building blocks (carboxylic acids) of the product. Each module corresponds to one building-block extension cycle. Type I PKSs resemble the yeast and animal fatty acid synthases (FASs), consisting of multi-domain polyproteins that form large multi-functional biosynthetic complexes, and act in either a modular or iterative fashion. Type II PKSs are putative multienzyme complexes consisting of discrete, separable proteins, like the FAS type II systems found in plants and bacteria. Type III PKSs (chalcone synthase-like enzymes) have a simple architecture that is a homodimer of identical ketoacyl synthase (KS) monomeric domains. Computational analyses of PKS proteins have provided valuable clues for development of knowledge-based methods for identification of catalytic domains in PKS and prediction of the substrate specificity for acyltransferase (AT) domains, which have led to some researchers for prediction of compound structures of PKs from sequence information of PKSs [2, 5]. However, those studies were performed with limited types of PKSs in limited numbers of organisms, and prediction of PKs made by some types of PKSs was not still successful. In this study, we have performed a cluster analysis of protein families in the all three types of PKSs from more than 800 genome-sequenced organisms to obtain the comprehensive perspective on the PKS diversification.