Venglustat Inhibits Protein N-Terminal Methyltransferase 1 in a Substrate-Competitive Manner.

ABSTRACT: Venglustat is a known allosteric inhibitor for ceramide glycosyltransferase, investigated in diseases caused by lysosomal dysfunction. Here, we identified venglustat as a potent inhibitor (IC₅₀ = 0.42 μM) of protein N-terminal methyltransferase 1 (NTMT1) by screening 58,130 compounds. Furthermore, venglustat exhibited selectivity for NTMT1 over 36 other methyltransferases. The crystal structure of NTMT1-venglustat and inhibition mechanism revealed that venglustat competitively binds at the peptide substrate site. Meanwhile, venglustat potently inhibited protein N-terminal methylation levels in cells (IC₅₀ = 0.5 μM). Preliminary structure-activity relationships indicated that the quinuclidine and fluorophenyl parts of venglustat are important for NTMT1 inhibition. In s

SUBMITTER: Dong G 

PROVIDER: S-EPMC9813856 | biostudies-literature | 2022 Sep

REPOSITORIES: biostudies-literature