6NZG

Bacteroides uniformis beta-glucuronidase 2 covalently bound to cyclophellitol-6-carboxylate aziridine

6NZG の概要

• エントリーDOI: 10.2210/pdb6nzg/pdb
• 分子名称: Beta-galactosidase, (1S,2R,3S,4S,5S,6R)-2-amino-3,4,5,6-tetrahydroxycyclohexane-1-carboxylic acid, GLYCEROL, ... (6 entities in total)
• 機能のキーワード: glycoside hydrolase family 2, beta-glucuronidase, activity-based probe, hydrolase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 由来する生物種: Bacteroides uniformis
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 202003.73

構造登録者

Pellock, S.J.,Jariwala, P.B.,Redinbo, M.R. (登録日: 2019-02-13, 公開日: 2019-12-18, 最終更新日: 2023-10-11)

主引用文献

Jariwala, P.B.,Pellock, S.J.,Goldfarb, D.,Cloer, E.W.,Artola, M.,Simpson, J.B.,Bhatt, A.P.,Walton, W.G.,Roberts, L.R.,Major, M.B.,Davies, G.J.,Overkleeft, H.S.,Redinbo, M.R.
Discovering the Microbial Enzymes Driving Drug Toxicity with Activity-Based Protein Profiling.
Acs Chem.Biol., 15:217-225, 2020

PubMed Abstract: It is increasingly clear that interindividual variability in human gut microbial composition contributes to differential drug responses. For example, gastrointestinal (GI) toxicity is not observed in all patients treated with the anticancer drug irinotecan, and it has been suggested that this variability is a result of differences in the types and levels of gut bacterial β-glucuronidases (GUSs). GUS enzymes promote drug toxicity by hydrolyzing the inactive drug-glucuronide conjugate back to the active drug, which damages the GI epithelium. Proteomics-based identification of the exact GUS enzymes responsible for drug reactivation from the complexity of the human microbiota has not been accomplished, however. Here, we discover the specific bacterial GUS enzymes that generate SN-38, the active and toxic metabolite of irinotecan, from human fecal samples using a unique activity-based protein profiling (ABPP) platform. We identify and quantify gut bacterial GUS enzymes from human feces with an ABPP-enabled proteomics pipeline and then integrate this information with kinetics to pinpoint the specific GUS enzymes responsible for SN-38 reactivation. Furthermore, the same approach also reveals the molecular basis for differential gut bacterial GUS inhibition observed between human fecal samples. Taken together, this work provides an unprecedented technical and bioinformatics pipeline to discover the microbial enzymes responsible for specific reactions from the complexity of human feces. Identifying such microbial enzymes may lead to precision biomarkers and novel drug targets to advance the promise of personalized medicine.

PubMed: 31774274
DOI: 10.1021/acschembio.9b00788

実験手法

X-RAY DIFFRACTION (2.43 Å)