Improving the Production of Epothilones by Precursors Addition Based on Metabolic Pathway Analysis

Abstract

Epothilones are a kind of poliketide macrolide with antifungal and anticancer bioactivity which are attracting more and more attention. However, despite a growing interest of epothilones, their practical use and research are very limited owing to the high production cost. Several studies have already demonstrated that yield of product can be affected by the addition of various precursors. In this paper, seven precursors of the biosynthesis of epothilones were analyzed by single-factor test and an L₉ 3⁴ orthogonal test. Finally, optimal condition led 1.55-fold of epothilone A and 1.46-fold of B increased in yields over that with the initial condition. The highest yields of epothilones were obtained in fermented culture with adding sodium acetate (80 mg/mL), sodium propionate (10 mg/mL), cysteine (20 mg/mL), and serine (60 mg/mL). The production profile under the optimized condition revealed that the serine, which could transform into cysteine and methylmalonyl-CoA, was the most significant precursor on the yields of both epothilones A and B. The result implied that the transformation of serine might be one of the key rate-limiting steps in the biosynthesis of epothilones.