Mechanism of action for small-molecule inhibitors of triacylglycerol synthesis

Inhibitors of triacylglycerol (TG) synthesis have shown promise in treating metabolic diseases, but their mechanisms remain unclear. This study uses cryo-EM to determine the structures of the TG synthesis enzyme DGAT1 in complex with two inhibitors, T863 and DGAT1IN1. Both inhibitors bind to DGAT1's fatty acyl-CoA substrate-binding tunnel, but with different modes of action. T863 blocks tunnel access, while DGAT1IN1 interacts with catalytic residues deeper within the enzyme. The study suggests an amide group as a common pharmacophore for inhibiting MBOATs. While minimally active against ACAT1, a single-residue mutation in ACAT1 increased sensitivity to inhibition, providing insights into inhibitor selectivity. This work forms a structural basis for future DGAT1 and MBOAT inhibitor development.

Xuewu Sui, Kun Wang, Kangkang Song, Chen Xu, Jiunn Song, Chia-Wei Lee, Maofu Liao, Robert V. Farese Jr., Tobias C. Walther