Biosynthesis of Trioxacarcin Revealing a Different Starter Unit and Complex Tailoring Steps for Type II Polyketide Synthase

Overview

Journal Chem Sci

Publisher Royal Society of Chemistry

Specialty Chemistry

Date 2018 Mar 8

PMID 29511509

Citations 14

Authors

Mei Zhang

Xian-Feng Hou

Li-Hua Qi

Yue Yin

Qing Li

Hai-Xue Pan

Xin-Ya Chen

Gong-Li Tang

Affiliations

Soon will be listed here.

Abstract

Trioxacarcins (TXNs) are highly oxygenated, polycyclic aromatic natural products with remarkable biological activity and structural complexity. Evidence from C-labelled precursor feeding studies demonstrated that the scaffold was biosynthesized from one unit of l-isoleucine and nine units of malonyl-CoA, which suggested a different starter unit in the biosynthesis. Genetic analysis of the biosynthetic gene cluster revealed 56 genes encoding a type II polyketide synthase (PKS), combined with a large amount of tailoring enzymes. Inactivation of seven post-PKS modification enzymes resulted in the production of a series of new TXN analogues, intermediates, and shunt products, most of which show high anti-cancer activity. Structural elucidation of these new compounds not only helps us to propose the biosynthetic pathway, featuring a type II PKS using a novel starter unit, but also set the stage for further characterization of the enzymatic reactions and combinatorial biosynthesis.

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