Formation of secondary allo-bile acids by novel enzymes from gut Firmicutes.
Formation of secondary allo-bile acids by novel enzymes from gut Firmicutes.
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来自肠道厚壁菌门的新酶形成次级同种异体胆汁酸。
DOI：
10.1080/19490976.2022.2132903
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发表时间：
2022-01
期刊：
影响因子：
12.2
通讯作者：
中科院分区：
文献类型：
--
作者：
脊椎动物的肠道微生物组能够进行胆汁酸的许多生物转化，胆汁酸负责肠道脂质消化并作为关键的营养信号分子发挥作用。人肝脏从胆固醇中产生胆汁酸，主要是A/B-顺式取向，其中甾醇环是“扭结的”，以及少量的A/B-反式取向的“平坦”立体异构体，称为“伯别胆汁酸”。虽然复杂的多步胆汁酸7α-脱羟基化途径已被充分研究，用于将“扭结”初级胆汁酸（例如胆酸（CA）和鹅去氧胆酸（CDCA））转化为去氧胆酸（DCA）和石胆酸（LCA），分别，形成“扁平”立体异构体别脱氧胆酸的酶促基础硬壁菌门（Firmicutes）的别-DCA（allo-DCA）和别-石胆酸（allo-LCA）问题三十年来一直未得到解决。在这里，我们提出了一种新的机制，厚壁菌产生的“平”胆汁酸allo-DCA和allo-LCA。BaiA 1催化3-oxo-allo-DCA最终还原为allo-DCA和3-oxo-allo-LCA最终还原为allo-LCA。对人类粪便样本的系统发育和宏基因组学分析表明，BaiP和BaiJ仅在厚壁菌门中编码，并且与最近报道的拟杆菌门中的膜相关胆汁酸5α-还原酶不同，所述膜相关胆汁酸5α-还原酶从3-氧代-Δ4-LCA间接产生allo-LCA。我们进一步绘制了人类宏基因组中厚壁菌门中baiP和baiJ的分布，证明了相对于健康个体，结直肠癌（CRC）患者中这两种基因的丰度增加。
The gut microbiome of vertebrates is capable of numerous biotransformations of bile acids, which are responsible for intestinal lipid digestion and function as key nutrient-signaling molecules. The human liver produces bile acids from cholesterol predominantly in the A/B-cis orientation in which the sterol rings are “kinked”, as well as small quantities of A/B-trans oriented “flat” stereoisomers known as “primary allo-bile acids”. While the complex multi-step bile acid 7α-dehydroxylation pathway has been well-studied for conversion of “kinked” primary bile acids such as cholic acid (CA) and chenodeoxycholic acid (CDCA) to deoxycholic acid (DCA) and lithocholic acid (LCA), respectively, the enzymatic basis for the formation of “flat” stereoisomers allo-deoxycholic acid (allo-DCA) and allo-lithocholic acid (allo-LCA) by Firmicutes has remained unsolved for three decades. Here, we present a novel mechanism by which Firmicutes generate the ”flat” bile acids allo-DCA and allo-LCA. The BaiA1 was shown to catalyze the final reduction from 3-oxo-allo-DCA to allo-DCA and 3-oxo-allo-LCA to allo-LCA. Phylogenetic and metagenomic analyses of human stool samples indicate that BaiP and BaiJ are encoded only in Firmicutes and differ from membrane-associated bile acid 5α-reductases recently reported in Bacteroidetes that indirectly generate allo-LCA from 3-oxo-Δ4-LCA. We further map the distribution of baiP and baiJ among Firmicutes in human metagenomes, demonstrating an increased abundance of the two genes in colorectal cancer (CRC) patients relative to healthy individuals.
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