9HTB

CutC in complex with inhibitor2

This is a non-PDB format compatible entry.

Summary for 9HTB

• Entry DOI: 10.2210/pdb9htb/pdb
• Descriptor: Choline trimethylamine-lyase, (3~{R})-3-ethynyl-1-azabicyclo[2.2.2]octan-3-ol, PHOSPHATE ION, ... (4 entities in total)
• Functional Keywords: cutc, inhibitor, tma lyase, oxidoreductase
• Biological source: Oleidesulfovibrio alaskensis
• Total number of polymer chains: 4
• Total formula weight: 361446.14

Authors

Petersen, J. (deposition date: 2024-12-19, release date: 2026-01-14, Last modification date: 2026-02-25)

Primary citation

Pettersson, M.,La Sala, G.,Gunnarsson, A.,Vildhede, A.,Sparklin, B.,Holm, B.,Petrovic, D.,Lasky, G.,Turick, S.,Szydlowska, M.,Gopalakrishnan, V.,Bake, T.,Petersen, J.,Branalt, J.,Westerlund, K.,Taillefer, M.,Henricsson, M.,Ek, M.,Warrener, P.,Roth, R.,Cohen, T.,Sjogren, T.,Fahlander, U.,Jurva, U.,Morias, Y.,Liddle, J.
Discovery of a Highly Potent and Selective Small-Molecule Inhibitor of In Vivo Anaerobic Choline Metabolism by Human Gut Bacteria.
J.Med.Chem., 69:2115-2129, 2026

PubMed Abstract: Trimethylamine (TMA) Lyase is an enzyme expressed in human gut bacteria that plays a pivotal role in the formation of trimethylamine oxide (TMAO), a metabolite implicated in the development of heart failure. Here, we describe a strategy to design covalent inhibitors targeting the active site thiyl radical involved in the catalytic cycle of the enzyme under anaerobic conditions. This strategy led to the discovery of , a previously unreported highly potent and selective inhibitor of TMA Lyase. When dosed orally to rats, shows a significant reduction of circulating TMAO levels and, importantly, demonstrates inhibition of TMAO generated from a human microbiome when profiled in a human fecal mouse transplant model.

PubMed: 41614677
DOI: 10.1021/acs.jmedchem.5c01451

Experimental method

X-RAY DIFFRACTION (1.584 Å)