Thermodynamic analysis of transition-state features in picomolar inhibitors of human 5'-methylthioadenosine phosphorylase.

ABSTRACT: Human 5'-methylthioadenosine phosphorylase (MTAP) is solely responsible for 5'-methylthioadenosine (MTA) metabolism to permit S-adenosylmethionine salvage. Transition-state (TS) analogues of MTAP are in development as anticancer candidates. TS analogues of MTAP incorporate a cationic nitrogen and a protonated 9-deazaadenine leaving group, which are mimics of the ribocation transition state. MT-ImmA and MT-DADMe-ImmA are two examples of these TS analogues. Thermodynamic analysis of MTA, inhibitor, and phosphate binding reveals the cationic nitrogen to provide -2.6 and -3.6 kcal/mol binding free energy for MT-ImmA and MT-DADMe-ImmA, respectively. The protonated deazaadenine provides an additional -1.3 (MT-ImmA) to -1.7 kcal/mol (MT-DADMe-ImmA). MT-DADMe-ImmA is a better match in TS geometry

SUBMITTER: Guan R 

PROVIDER: S-EPMC3870587 | biostudies-literature | 2013 Nov

REPOSITORIES: biostudies-literature