Biosynthesis of clinically used antibiotic fusidic acid and identification of two short-chain dehydrogenase/reductases with converse stereoselectivity

Zhiqin Cao; Shaoyang Li; Jianming Lv; Hao Gao; Guodong Chen; Takayoshi Awakawa; Ikuro Abe; Xinsheng Yao; Dan Hu

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Biosynthesis of clinically used antibiotic fusidic acid and identification of two short-chain dehydrogenase/reductases with converse stereoselectivity

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Fusidic acid is the only fusidane-type antibiotic that has been clinically used.However,biosynthesis of this important molecule in fungi is poorly understood.We have recently elucidated the biosynthesis of fusidane-type antibiotic helvolic acid,which provides us with clues to identify a possible gene cluster for fusidic acid (fus cluster).This gene cluster consists of eight genes,among which six are conserved in the helvolic acid gene cluster exceptfusC1 andfusB1.Introduction of the two genes into the Aspergillus oryzae NSAR1 expressing the conserved six genes led to the production of fusidic acid.A stepwise introduction offusC1 and fusBl revealed that the two genes worked independently without a strict reaction order.Notably,we identified two short-chain dehydrogenase/reductase genes fusC1 and fusC2 in thefus cluster,which showed converse stereoselectivity in 3-ketoreduction.This is the first report on the biosynthesis and heterologous expression of fusidic acid.

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《药学学报（英文版）》 |2019年第2期|433-442|共10页
作者
Zhiqin Cao; Shaoyang Li; Jianming Lv; Hao Gao; Guodong Chen; Takayoshi Awakawa; Ikuro Abe; Xinsheng Yao; Dan Hu;
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Institute of Traditional Chinese Medicine and Natural Products, College of Pharmacy/Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, Jinan University, Guangzhou 510632, China;

Institute of Traditional Chinese Medicine and Natural Products, College of Pharmacy/Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, Jinan University, Guangzhou 510632, China;

Institute of Traditional Chinese Medicine and Natural Products, College of Pharmacy/Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, Jinan University, Guangzhou 510632, China;

Institute of Traditional Chinese Medicine and Natural Products, College of Pharmacy/Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, Jinan University, Guangzhou 510632, China;

Institute of Traditional Chinese Medicine and Natural Products, College of Pharmacy/Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, Jinan University, Guangzhou 510632, China;

Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan;

Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan;

Institute of Traditional Chinese Medicine and Natural Products, College of Pharmacy/Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, Jinan University, Guangzhou 510632, China;

Institute of Traditional Chinese Medicine and Natural Products, College of Pharmacy/Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, Jinan University, Guangzhou 510632, China;

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Biosynthesis of clinically used antibiotic fusidic acid and identification of two short-chain dehydrogenase/reductases with converse stereoselectivity

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