Cell-Effective Transition-State Analogue of Phenylethanolamine N-Methyltransferase.

ABSTRACT: Phenylethanolamine N-methyltransferase (PNMT) catalyzes the S-adenosyl-l-methionine (SAM)-dependent methylation of norepinephrine to form epinephrine. Epinephrine is implicated in the regulation of blood pressure, respiration, Alzheimer's disease, and post-traumatic stress disorder (PTSD). Transition-state (TS) analogues bind their target enzymes orders of magnitude more tightly than their substrates. A synthetic strategy for first-generation TS analogues of human PNMT (hPNMT) permitted structural analysis of hPNMT and revealed potential for second-generation inhibitors [Mahmoodi, N.; J. Am. Chem. Soc. 2020, 142, 14222-14233]. A second-generation TS analogue inhibitor of PNMT was designed, synthesized, and characterized to yield a K_i value of 1.2 nM.

SUBMITTER: Mahmoodi N 

PROVIDER: S-EPMC10646973 | biostudies-literature | 2023 Aug

REPOSITORIES: biostudies-literature