Biosynthesis of clinically used antibiotic fusidic acid and identification of two short-chain dehydrogenase/reductases with converse stereoselectivity
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...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2019-03-01
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| Series: | Acta Pharmaceutica Sinica B |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211383518308062 |
| _version_ | 1818175802738475008 |
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| author | Zhiqin Cao Shaoyang Li Jianming Lv Hao Gao Guodong Chen Takayoshi Awakawa Ikuro Abe Xinsheng Yao Dan Hu |
| author_facet | Zhiqin Cao Shaoyang Li Jianming Lv Hao Gao Guodong Chen Takayoshi Awakawa Ikuro Abe Xinsheng Yao Dan Hu |
| author_sort | Zhiqin Cao |
| collection | DOAJ |
| description | 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 |
| first_indexed | 2024-12-11T20:06:05Z |
| format | Article |
| id | doaj.art-a809b3780b4d4c5295a2b7fddc6d7f30 |
| institution | Directory Open Access Journal |
| issn | 2211-3835 |
| language | English |
| last_indexed | 2024-12-11T20:06:05Z |
| publishDate | 2019-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Acta Pharmaceutica Sinica B |
| spelling | doaj.art-a809b3780b4d4c5295a2b7fddc6d7f302022-12-22T00:52:24ZengElsevierActa Pharmaceutica Sinica B2211-38352019-03-0192433442Biosynthesis of clinically used antibiotic fusidic acid and identification of two short-chain dehydrogenase/reductases with converse stereoselectivityZhiqin Cao0Shaoyang Li1Jianming Lv2Hao Gao3Guodong Chen4Takayoshi Awakawa5Ikuro Abe6Xinsheng Yao7Dan Hu8Institute 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, ChinaInstitute 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, ChinaInstitute 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, ChinaInstitute 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, ChinaInstitute 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, ChinaGraduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, JapanGraduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, JapanInstitute 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; Corresponding authors.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; Corresponding authors.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, SDRhttp://www.sciencedirect.com/science/article/pii/S2211383518308062 |
| spellingShingle | 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 Acta Pharmaceutica Sinica B |
| title | Biosynthesis of clinically used antibiotic fusidic acid and identification of two short-chain dehydrogenase/reductases with converse stereoselectivity |
| title_full | Biosynthesis of clinically used antibiotic fusidic acid and identification of two short-chain dehydrogenase/reductases with converse stereoselectivity |
| title_fullStr | Biosynthesis of clinically used antibiotic fusidic acid and identification of two short-chain dehydrogenase/reductases with converse stereoselectivity |
| title_full_unstemmed | Biosynthesis of clinically used antibiotic fusidic acid and identification of two short-chain dehydrogenase/reductases with converse stereoselectivity |
| title_short | Biosynthesis of clinically used antibiotic fusidic acid and identification of two short-chain dehydrogenase/reductases with converse stereoselectivity |
| title_sort | biosynthesis of clinically used antibiotic fusidic acid and identification of two short chain dehydrogenase reductases with converse stereoselectivity |
| url | http://www.sciencedirect.com/science/article/pii/S2211383518308062 |
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