6D4O

Eubacterium eligens beta-glucuronidase bound to an amoxapine-glucuronide conjugate

Summary for 6D4O

• Entry DOI: 10.2210/pdb6d4o/pdb
• Descriptor: Beta-glucuronidase, (5aR,9aR)-2-chloro-11-(4-beta-D-glucopyranuronosylpiperazin-1-yl)-5a,6,9,9a-tetrahydrodibenzo[b,f][1,4]oxazepine, CHLORIDE ION, ... (5 entities in total)
• Functional Keywords: glycosyl hydrolase, hydrolase
• Biological source: [Eubacterium] eligens
• Total number of polymer chains: 1
• Total formula weight: 70387.50

Authors

Pellock, S.J.,Walton, W.G.,Redinbo, M.R. (deposition date: 2018-04-18, release date: 2018-07-25, Last modification date: 2024-03-13)

Primary citation

Pellock, S.J.,Creekmore, B.C.,Walton, W.G.,Mehta, N.,Biernat, K.A.,Cesmat, A.P.,Ariyarathna, Y.,Dunn, Z.D.,Li, B.,Jin, J.,James, L.I.,Redinbo, M.R.
Gut Microbial beta-Glucuronidase Inhibition via Catalytic Cycle Interception.
ACS Cent Sci, 4:868-879, 2018

PubMed Abstract: Microbial β-glucuronidases (GUSs) cause severe gut toxicities that limit the efficacy of cancer drugs and other therapeutics. Selective inhibitors of bacterial GUS have been shown to alleviate these side effects. Using structural and chemical biology, mass spectrometry, and cell-based assays, we establish that piperazine-containing GUS inhibitors intercept the glycosyl-enzyme catalytic intermediate of these retaining glycosyl hydrolases. We demonstrate that piperazine-based compounds are substrate-dependent GUS inhibitors that bind to the GUS-GlcA catalytic intermediate as a piperazine-linked glucuronide (GlcA, glucuronic acid). We confirm the GUS-dependent formation of inhibitor-glucuronide conjugates by LC-MS and show that methylated piperazine analogs display significantly reduced potencies. We further demonstrate that a range of approved piperazine- and piperidine-containing drugs from many classes, including those for the treatment of depression, infection, and cancer, function by the same mechanism, and we confirm through gene editing that these compounds selectively inhibit GUS in living bacterial cells. Together, these data reveal a unique mechanism of GUS inhibition and show that a range of therapeutics may impact GUS activities in the human gut.

PubMed: 30062115
DOI: 10.1021/acscentsci.8b00239

Experimental method

X-RAY DIFFRACTION (2.9 Å)