Cyclization Specificity of Polyketide Synthase

Ring formation is a common strategy to diversify natural products, and the molecular basis of cyclization specificity is a vigorously pursued topic in natural product biosynthesis. Polyketides are a class of natural products with highly diverse chemical structures and pharmaceutical activities. Polyketide cyclization, promoted by the aromatase/cyclase (ARO/CYC) in bacterial aromatic polyketide synthase (PKS) and the PT domain in fungal PKS, helps diversify polyketides. How the ARO/CYC and PT domain promotes highly specific cyclization is not well understood. Herein we present the crystal structures of Tcm ARO/CYC and the aflatoxin pksA PT domains. Although the two proteins share less than 15% of sequence identity, the crystal structures reveal a striking similarity in the overall fold, substrate cavity and cyclization mechanism. The critical comparison allows a rationale behind the vast cyclization diversity observed in polyketide natural products.