降解黏液的肠道共生菌嗜黏液阿克曼氏菌药物再激活β-葡糖苷酶的结构-功能研究。

IF 2.7 3区 生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY
Tarushi, Gagan Deep Gupta, Mukesh Kumar, Subhash C Bihani
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引用次数: 0

摘要

肠道微生物β-葡萄糖醛酸酶(mGUS)不仅调节多种激素和神经递质,还影响外源药物的疗效和毒性。在某些抗癌药物上,如伊立替康(irinotecan, SN-38), mGUS活性导致肠肝再循环,导致严重腹泻。本文报道了一种新型β-葡糖醛酸酶AmGUS的表达、纯化和鉴定。嗜muciniphila是一种重要的肠道共生体,对代谢健康和肠道稳态具有有益作用。AmGUS对无葡萄糖苷酶或半乳糖糖苷酶活性的葡萄糖醛酸底物具有特异性。有趣的是,它还显示了抗癌药物SN38的葡萄糖醛酸化形式的有效裂解,可能导致其肠肝再循环。此外,我们发现AmGUS酶作为单体发挥作用,与其他GUS酶作为低聚物存在相反。根据提供底物特异性的保守核心周围不同的活性位点环,mGUS被分为不同的环类型。AmGUS结构的计算模型显示,尽管与mL1环型和nl型GUS具有显著的序列/结构相似性,但它属于mL2环型GUS酶。有趣的是,AmGUS也有一个独特的n端环,以前在任何其他GUS酶中都没有观察到,可能有助于药物葡萄糖醛酸苷的加工。综上所述,这些发现表明嗜粘杆菌的GUS属于一类新的GUS酶,具有独特的活性位点环结构。这种独特的GUS酶的存在可能有助于嗜粘杆菌在人肠道定植。总的来说,这项研究拓宽了我们对人类肠道微生物群中GUSome的结构和功能的认识。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Structure-function studies on drug-reactivating β-glucuronidase from mucin-degrading gut symbiont Akkermansia muciniphila.

Gut microbial β-glucuronidases (mGUS) not only regulate several hormones and neurotransmitters, they also impact the efficacy and toxicity of xenobiotics. On certain anticancer drugs, e.g. irinotecan (SN-38), mGUS activity leads to enterohepatic recirculation resulting into severe diarrhea. Here, we report the expression, purification and characterization of AmGUS, a novel β-glucuronidase from Akkermansia muciniphila. A. muciniphila is a prominent gut symbiont with beneficial effects on metabolic health and gut homeostasis. AmGUS demonstrates specificity towards glucuronide substrates with no glucosidase or galactosidase activity. Interestingly, it also shows efficient cleavage of the glucuronidated form of the anti-cancer drug, SN38, potentially leading to its enterohepatic recirculation. Furthermore, we find that AmGUS functions as a monomer, contrary to other GUS enzymes that exist as oligomers. mGUS are classified into distinct loop-types based on different active site loops around a conserved core providing substrate specificity. Computational modeling of AmGUS structure reveals that it belongs to the mL2 loop-type GUS enzymes, despite sharing significant sequence/structural similarity with the mL1 loop-type and NL-type GUSs. Interestingly, AmGUS also has a unique N-terminal loop previously not observed in any other GUS enzyme possibly aiding in the processing of drug-glucuronides. Together, these findings suggest that GUS from A. muciniphila belongs to a new class of GUS enzymes with unique active site loop structures. The presence of this unique GUS enzyme may help A. muciniphila in colonizing the human gut. Overall, this study broadens our knowledge of the structural and functional understanding of GUSome in the human gut microbiome.

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来源期刊
Journal of Biomolecular Structure & Dynamics
Journal of Biomolecular Structure & Dynamics 生物-生化与分子生物学
CiteScore
8.90
自引率
9.10%
发文量
597
审稿时长
2 months
期刊介绍: The Journal of Biomolecular Structure and Dynamics welcomes manuscripts on biological structure, dynamics, interactions and expression. The Journal is one of the leading publications in high end computational science, atomic structural biology, bioinformatics, virtual drug design, genomics and biological networks.
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