小柯机器人

美国密歇根州立大学Robert A. Quinn研究小组发现，胆汁盐水解酶酰基转移酶活性扩大胆汁酸的多样性。相关论文于2024年2月7日在线发表于国际学术期刊《自然》。

研究人员确定了肠道微生物群代谢胆汁酸的酶，该机制涉及氨基酸与胆汁酸酰基位点的结合，从而产生多种微生物结合胆汁酸（MCBA）。研究表明，这种转化是由胆盐水解酶（胆盐水解酶/转移酶，BSH/T）的酰基转移酶活性介导的。产气荚膜梭菌BSH/T在获得各种氨基酸和牛胆酸盐、甘油胆酸盐或胆酸盐后可迅速进行酰基转移，在pH值为5.3时效果最佳。产气荚膜杆菌BSH/T的氨基酸结合作用多种多样，包括除脯氨酸和天冬氨酸以外的所有蛋白氨基酸。肠道细菌普遍产生MCBA，氨基酸的使用具有菌株特异性。具有相似BSH/T氨基酸序列的菌种具有相似的结合谱，一些bsh/t等位基因与结合多样性的增加相关。BSH/T的三级结构图以及诱变实验表明，活性位点结构会影响氨基酸的选择性。

这些MCBA产物具有抗菌特性，其中氨基酸疏水性越强，抗菌活性越高。MCBA的抑制浓度达到了在哺乳动物肠道中测得的水平。喂给小鼠的MCBA进入肠肝循环，其中肝脏和胆囊中的浓度因结合氨基酸而异。对人类粪便样本中的MCBA进行定量分析后发现，它们的浓度等于或高于二级和一级胆汁酸（BA），并且在减肥手术后会减少，从而证明MCBA是BA库中的重要组成部分，可因胃肠道生理变化而改变。总之，BSH/T固有的酰基转移酶活性极大地丰富了BA化学成分，产生了一系列以前未被重视的代谢物，有可能影响微生物组和人体健康。

研究人员表示，BA是胆汁中的类固醇去垢剂，有助于脂肪和脂溶性维生素的吸收，同时因其抗菌特性而塑造肠道微生物群。

附：英文原文

Title: Bile salt hydrolase acyltransferase activity expands bile acid diversity

Author: Guzior, Douglas V., Okros, Maxwell, Shivel, Madison, Armwald, Bruin, Bridges, Christopher, Fu, Yousi, Martin, Christian, Schilmiller, Anthony L., Miller, Wendy M., Ziegler, Kathryn M., Sims, Matthew D., Maddens, Michael E., Graham, Stewart F., Hausinger, Robert P., Quinn, Robert A.

Issue&Volume: 2024-02-07

Abstract: Bile acids (BAs) are steroid detergents in bile that contribute to the absorption of fats and fat-soluble vitamins while shaping the gut microbiome because of their antimicrobial properties1,2,3,4. Here we identify the enzyme responsible for a mechanism of BA metabolism by the gut microbiota involving amino acid conjugation to the acyl-site of BAs, thus producing a diverse suite of microbially conjugated bile acids (MCBAs). We show that this transformation is mediated by acyltransferase activity of bile salt hydrolase (bile salt hydrolase/transferase, BSH/T). Clostridium perfringens BSH/T rapidly performed acyl transfer when provided various amino acids and taurocholate, glycocholate or cholate, with an optimum at pH5.3. Amino acid conjugation by C. perfringens BSH/T was diverse, including all proteinaceous amino acids except proline and aspartate. MCBA production was widespread among gut bacteria, with strain-specific amino acid use. Species with similar BSH/T amino acid sequences had similar conjugation profiles and several bsh/t alleles correlated with increased conjugation diversity. Tertiary structure mapping of BSH/T followed by mutagenesis experiments showed that active site structure affects amino acid selectivity. These MCBA products had antimicrobial properties, where greater amino acid hydrophobicity showed greater antimicrobial activity. Inhibitory concentrations of MCBAs reached those measured natively in the mammalian gut. MCBAs fed to mice entered enterohepatic circulation, in which liver and gallbladder concentrations varied depending on the conjugated amino acid. Quantifying MCBAs in human faecal samples showed that they reach concentrations equal to or greater than secondary and primary BAs and were reduced after bariatric surgery, thus supporting MCBAs as a significant component of the BA pool that can be altered by changes in gastrointestinal physiology. In conclusion, the inherent acyltransferase activity of BSH/T greatly diversifies BA chemistry, creating a set of previously underappreciated metabolites with the potential to affect the microbiome and human health.

DOI: 10.1038/s41586-024-07017-8

Source: https://www.nature.com/articles/s41586-024-07017-8

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
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