Dissection, Optimization, and Structural Analysis of a Covalent Irreversible DDAH1 Inhibitor.

ABSTRACT: Inhibitors of the human enzyme dimethylarginine dimethylaminohydrolase-1 (DDAH1) can control endogenous nitric oxide production. A time-dependent covalent inactivator of DDAH1, N⁵-(1-imino-2-chloroethyl)-l-ornithine ( K_I = 1.3 μM, k_inact = 0.34 min^-1), was conceptually dissected into two fragments and each characterized separately: l-norvaline ( K_i = 470 μM) and 2-chloroacetamidine ( K_I = 310 μM, k_inact = 4.0 min^-1). This analysis suggested that the two fragments were not linked in a manner that allows either to reach full affinity or reactivity, prompting the synthesis and characterization of three analogues: two that mimic the dimethylation status of the substrate, N⁵-(1-imino-2-chloroisopr

SUBMITTER: Burstein-Teitelbaum G 

PROVIDER: S-EPMC6074031 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature