8GER

E. eligens beta-glucuronidase bound to norquetiapine-glucuronide

Summary for 8GER

• Entry DOI: 10.2210/pdb8ger/pdb
• Descriptor: Beta-glucuronidase, 11-(4-beta-D-glucopyranuronosylpiperazin-1-yl)dibenzo[b,f][1,4]thiazepine (3 entities in total)
• Functional Keywords: beta-glucuronidase, inhibitor, glucuronide, hydrolase
• Biological source: Lachnospira eligens
• Total number of polymer chains: 1
• Total formula weight: 70306.64

Authors

Simpson, J.B.,Lietzan, A.D.,Redinbo, M.R. (deposition date: 2023-03-07, release date: 2024-03-20, Last modification date: 2024-06-26)

Primary citation

Simpson, J.B.,Walker, M.E.,Sekela, J.J.,Ivey, S.M.,Jariwala, P.B.,Storch, C.M.,Kowalewski, M.E.,Graboski, A.L.,Lietzan, A.D.,Walton, W.G.,Davis, K.A.,Cloer, E.W.,Borlandelli, V.,Hsiao, Y.C.,Roberts, L.R.,Perlman, D.H.,Liang, X.,Overkleeft, H.S.,Bhatt, A.P.,Lu, K.,Redinbo, M.R.
Gut microbial beta-glucuronidases influence endobiotic homeostasis and are modulated by diverse therapeutics.
Cell Host Microbe, 32:925-944.e10, 2024

PubMed Abstract: Hormones and neurotransmitters are essential to homeostasis, and their disruptions are connected to diseases ranging from cancer to anxiety. The differential reactivation of endobiotic glucuronides by gut microbial β-glucuronidase (GUS) enzymes may influence interindividual differences in the onset and treatment of disease. Using multi-omic, in vitro, and in vivo approaches, we show that germ-free mice have reduced levels of active endobiotics and that distinct gut microbial Loop 1 and FMN GUS enzymes drive hormone and neurotransmitter reactivation. We demonstrate that a range of FDA-approved drugs prevent this reactivation by intercepting the catalytic cycle of the enzymes in a conserved fashion. Finally, we find that inhibiting GUS in conventional mice reduces free serotonin and increases its inactive glucuronide in the serum and intestines. Our results illuminate the indispensability of gut microbial enzymes in sustaining endobiotic homeostasis and indicate that therapeutic disruptions of this metabolism promote interindividual response variabilities.

PubMed: 38754417
DOI: 10.1016/j.chom.2024.04.018

Experimental method

X-RAY DIFFRACTION (2.4 Å)