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Characterization of the mechanism of bile salt hydrolase substrate specificity by experimental and computational analyses

文献类型： 外文期刊

作者： Karlov, Dmitry S. 1 ; Long, Sarah L. 2 ; Zeng, Ximin 4 ; Xu, Fuzhou 4 ; Lal, Kanhaya 1 ; Cao, Liu 4 ; Hayoun, Karim 2 ; Lin, Jun 4 ; Joyce, Susan A. 2 ; Tikhonova, Irina G. 1 ;

作者机构： 1.Queens Univ Belfast, Med Biol Ctr, Sch Pharm, Belfast BT9 7BL, North Ireland

2.Univ Coll Cork, Sch Biochem & Cell Biol, Cork T12 YT20, Ireland

3.Univ Coll Cork, APC Microbiome Ireland, Cork T12 YT20, Ireland

4.Univ Tennessee, Dept Anim Sci, Knoxville, TN 37996 USA

5.Inst Anim Husb & Vet Med, Beijing Acad Agr & Forestry Sci, Beijing 100097, Peoples R China

期刊名称：STRUCTURE （ 影响因子：5.7； 五年影响因子：5.1 ）

ISSN： 0969-2126

年卷期： 2023 年 31 卷 5 期

页码：

收录情况： SCI

摘要： Bile salt hydrolases (BSHs) are currently being investigated as target enzymes for metabolic regulators in hu-mans and as growth promoters in farm animals. Understanding structural features underlying substrate specificity is necessary for inhibitor design. Here, we used a multidisciplinary workflow including mass spec-trometry, mutagenesis, molecular dynamic simulations, machine learning, and crystallography to demon-strate substrate specificity in Lactobacillus salivarius BSH, the most abundant enzyme in human and farm animal intestines. We show the preference of substrates with a taurine head and a dehydroxylated sterol ring for hydrolysis. A regression model that correlates the relative rates of hydrolysis of various substrates in various enzyme mutants with the residue-substrate interaction energies guided the identification of structural determinants of substrate binding and specificity. In addition, we found T208 from another BSH protomer regulating the hydrolysis. The designed workflow can be used for fast and comprehensive charac-terization of enzymes with a broad range of substrates.

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