Citation: Fan Yafei, Zhang E, Guo Heng, Mu Ning, Chen Dandan, Wang Wengui, Wang Shoufeng, Liu Wen. Insights into the Substrate Tolerance of Enzymes Involved in the Nosiheptide Biosynthesis Pathway Based on Indolic Acid Moiety[J]. Chinese Journal of Organic Chemistry, ;2020, 40(11): 3828-3836. doi: 10.6023/cjoc202006059 shu

Insights into the Substrate Tolerance of Enzymes Involved in the Nosiheptide Biosynthesis Pathway Based on Indolic Acid Moiety

Fan Yafei ^a ,
Zhang E ^a ,
Guo Heng ^b ,
Mu Ning ^a ,
Chen Dandan ^b ,
Wang Wengui ^a ,
Wang Shoufeng ^a,, ,
Liu Wen ^b,c,,

a.
Shandong Provincial Key Laboratory of Fluorine Chemistry and Chemical Materials, School of Chemistry and Chemical Engineering, University of Jinan, Jinan 250022
b.
State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032
c.
Huzhou Center of Bio-Synthetic Innovation, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Huzhou, Zhejiang 313000

Corresponding author: Wang Shoufeng, chm_wangsf@ujn.edu.cn Liu Wen, wliu@mail.sioc.ac.cn
Received Date: 28 June 2020
Revised Date: 6 August 2020
Available Online: 8 September 2020
Fund Project: the Chinese Academy of Sciences XDB20020200the Shandong Key Research Program 2019GSF108223the Youth Innovation Promotion Association of the Chinese Academy of Sciences 2017303Project supported by the National Natural Science Foundation of China (Nos.31972850, 21750004, 21520102004), the Shandong Key Research Program (No. 2019GSF108223), the Chinese Academy of Sciences (Nos.QYZDJ-SSW-SLH037, XDB20020200), the Science and Technology Commission of Shanghai Municipality (No.17JC1405100), the Youth Innovation Promotion Association of the Chinese Academy of Sciences (No.2017303), the State Key Laboratory of Microbial Technology Open Projects Fund (No.M2020-05) and the K.C.Wong Education Foundationthe Science and Technology Commission of Shanghai Municipality 17JC1405100the Chinese Academy of Sciences QYZDJ-SSW-SLH037the State Key Laboratory of Microbial Technology Open Projects Fund M2020-05the National Natural Science Foundation of China 21520102004the National Natural Science Foundation of China 31972850the National Natural Science Foundation of China 21750004

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As a typical representative of thiopeptide antibiotics, nosiheptide (NOS) possesses very good antibacterial activity. However, due to poor water solubility and low bioavailability, its clinical application is hampered. Due to its complex structure, it is difficult to obtain analogues with improved physical and chemical properties via total chemical synthesis. Based on the previous studies on the biosynthesis of nosiheptide, the side-ring 3-methyl-2-indoleic acid (MIA) analogues were used as chemical small molecule probes to explore the substrate tolerance of enzymes involved in NOS biosynthesis pathway in NOS-producing bacteria via the co-fermentation of probe molecules with mutant strain and the combination of high resolution mass spectrometry data of fermentation products. The results showed that enzymes involved in NOS biosynthesis pathway had a considerable tolerance to MIA analogues substituted by F, Cl and CH₃, however, MIA analogues substituted by large steric hindrance group, such as NO₂, CF₃ and Ph, were not tolerated. The position, the size and the property of the substituted groups of MIA also affected the steps of identification, transport and upload of the related enzymes involved in NOS biosynthesis. The present study not only explored the substrate tolerance of enzymes involved in NOS biosynthesis pathway, but also was expected to obtain NOS analogues via biosynthetic pathway engineering. What's more, it provides valuable information for using directed evolution technology to improve the substrate tolerance of enzymes in the rate-limiting steps of NOS biosynthesis and to expand the use of NOS-producing bacteria to obtain more analogues.
- nosiheptide,
- 3-methyl-2-indolic acid,
- mutational biosynthesis,
- chemical small molecule probe,
- substrate tolerance of enzymes
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