New insights into bacterial type II polyketide biosynthesis.

Zhuan Zhang,Hai-Xue Pan,Gong-Li Tang

doi:10.12688/f1000research.10466.1

Abstract

Bacterial aromatic polyketides, exemplified by anthracyclines, angucyclines, tetracyclines, and pentangular polyphenols, are a large family of natural products with diverse structures and biological activities and are usually biosynthesized by type II polyketide synthases (PKSs). Since the starting point of biosynthesis and combinatorial biosynthesis in 1984–1985, there has been a continuous effort to investigate the biosynthetic logic of aromatic polyketides owing to the urgent need of developing promising therapeutic candidates from these compounds. Recently, significant advances in the structural and mechanistic identification of enzymes involved in aromatic polyketide biosynthesis have been made on the basis of novel genetic, biochemical, and chemical technologies. This review highlights the progress in bacterial type II PKSs in the past three years (2013–2016). Moreover, novel compounds discovered or created by genome mining and biosynthetic engineering are also included.

Highlights

Type II polyketide biosynthesis usually begins by loading an α-carboxylated precursor, normally acetate, onto an acyl carrier protein (ACP), which is subsequently transferred to the active site of a ketosynthase (KS) and undergoes iterative elongation using malonyl-coenzyme A (CoA) as extender units to afford a nascent poly-β-keto chain[1,2,3]
Mechanistic studies of polyketide biosynthesis have made great progress in the past decade; because of emerging antibiotic and anticancer drug resistance, there is a need to unravel the chemical logic and molecular machinery involved in the biosynthetic pathway; this will form the basis of engineering natural product assembly lines to generate bioactive compounds that could lead to clinical candidates
A growing number of crystal structures of enzymes involved in type II polyketide biosynthesis have been elucidated, which contributes a lot to mechanistic characterization and enables the study of enzymatic evolution at the structural level and provides structural diversities when combined with chemical synthesis

Summary

Introduction

Type II polyketide biosynthesis usually begins by loading an α-carboxylated precursor, normally acetate, onto an acyl carrier protein (ACP), which is subsequently transferred to the active site of a ketosynthase (KS) and undergoes iterative elongation using malonyl-coenzyme A (CoA) as extender units to afford a nascent poly-β-keto chain[1,2,3]. Recent advances in enzymes responsible for the formation of aromatic polyketide skeletons An essential strategy to provide structurally diverse natural products is to employ different starter units. The crystal structure of AuaEII, the anthranilate-CoA ligase involved in generating anthraniloyl-CoA, which acts as a starter unit during a type II polyketide synthase (PKS) pathway in aurachin biosynthesis, was reported by Tsai’s group (Figure 1)[6]. Three non-reducing mono-domain AROs/ CYCs – TcmN (C9–C14), ZhuI (C7–C12), and WhiE (C9–C14) – have been reported by Tsai and co-workers in the past few years Just recently, they presented the crystal structures of two di-domain AROs/CYCs: StfQ (non-reducing C7–C12) and BexL (reducing C7–C12)[7]. This work greatly enriches our knowledge of the structures and functions of mono- and di-domain AROs/CYCs in bacterial PKSs. During the biosynthesis of four-ring aromatic polyketides, the fourth ring CYC catalyzes the last ring’s formation to afford the primary polyketide core.

H OCH3 OH

Conclusion

Hertweck C