Original Articles
Zhiqin Cao, Shaoyang Li, Jianming Lv, Hao Gao, Guodong Chen, Takayoshi Awakawa, Ikuro Abe, Xinsheng Yao, Dan Hu. Biosynthesis of clinically used antibiotic fusidic acid and identification of two short-chain dehydrogenase/reductases with converse stereoselectivity[J]. Acta Pharmaceutica Sinica B, 2019, 9(2): 433-442

Biosynthesis of clinically used antibiotic fusidic acid and identification of two short-chain dehydrogenase/reductases with converse stereoselectivity
Zhiqin Caoa, Shaoyang Lia, Jianming Lva, Hao Gaoa, Guodong Chena, Takayoshi Awakawab, Ikuro Abeb, Xinsheng Yaoa, Dan Hua
a 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;
b Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
Abstract:
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 except fusC1 and fusB1. 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 of fusC1 and fusB1 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 the fus cluster, which showed converse stereoselectivity in 3-ketoreduction. This is the first report on the biosynthesis and heterologous expression of fusidic acid.
Key words:    Biosynthesis    Fungi    Fusidic acid    Fusidane-type antibiotics    SDR   
Received: 2018-08-17     Revised: 2018-10-17
DOI: 10.1016/j.apsb.2018.10.007
Funds: We thank Professor K.Gomi (Tohoku University) and Professor K.Kitamoto (The University of Tokyo) for the Aspergillus oryzae NSAR1 heterologous expression system.This work was mainly supported by grants from the National Natural Science Foundation of China (31870032,3171101305,and 31670036);the 111 Project of Ministry of Education of the People's Republic of China (B13038);the JST/NSFC Strategic International Collaborative Research Program;Japanese-Chinese Collaborative Research Program;Chang Jiang Scholars Program (Hao Gao,2017) from the Ministry of Education of China;Guangdong Special Support Program (2016TX03R280);Guangdong Province Universities and Colleges Pearl River Scholar Funded Scheme (Hao Gao,2014);and K.C.Wong Education Foundation (Hao Gao,2016);Guangzhou Science and Technology Project (201707010266,China);the Fundamental Research Funds for the Central Universities (21617495);Kobayashi International Scholarship Foundation;a Grant-in-Aid for Scientific Research from the Ministry of Education,Culture,Sports,Science and Technology,Japan (JSPS KAKENHI Grant Number JP15H01836 and JP16H06443).
Corresponding author: Xinsheng Yao, Dan Hu     Email:tyaoxs@jnu.edu.cn;thudan@jnu.edu.cn
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Zhiqin Cao
Shaoyang Li
Jianming Lv
Hao Gao
Guodong Chen
Takayoshi Awakawa
Ikuro Abe
Xinsheng Yao
Dan Hu

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