Tarushi, Gagan Deep Gupta, Mukesh Kumar, Subhash C Bihani
{"title":"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。","authors":"Tarushi, Gagan Deep Gupta, Mukesh Kumar, Subhash C Bihani","doi":"10.1080/07391102.2025.2496291","DOIUrl":null,"url":null,"abstract":"<p><p>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 <i>Akkermansia muciniphila. A. muciniphila</i> 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 <i>A. muciniphila</i> belongs to a new class of GUS enzymes with unique active site loop structures. The presence of this unique GUS enzyme may help <i>A. muciniphila</i> in colonizing the human gut. Overall, this study broadens our knowledge of the structural and functional understanding of GUSome in the human gut microbiome.</p>","PeriodicalId":15272,"journal":{"name":"Journal of Biomolecular Structure & Dynamics","volume":" ","pages":"1-15"},"PeriodicalIF":2.7000,"publicationDate":"2025-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Structure-function studies on drug-reactivating β-glucuronidase from mucin-degrading gut symbiont <i>Akkermansia muciniphila</i>.\",\"authors\":\"Tarushi, Gagan Deep Gupta, Mukesh Kumar, Subhash C Bihani\",\"doi\":\"10.1080/07391102.2025.2496291\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>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 <i>Akkermansia muciniphila. A. muciniphila</i> 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 <i>A. muciniphila</i> belongs to a new class of GUS enzymes with unique active site loop structures. The presence of this unique GUS enzyme may help <i>A. muciniphila</i> in colonizing the human gut. 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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.
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.