L337H mutant of rat neuronal nitric oxide synthase resembles human neuronal nitric oxide synthase toward inhibitors.
A common dichotomy exists in inhibitor design: should the compounds be designed to block the enzymes of animals in the preclinical studies or to inhibit the human enzyme? We report that a single mutation of Leu-337 in rat neuronal nitric oxide synthase (nNOS) to His makes the enzyme resemble human nNOS more than rat nNOS. We expect that the approach used in this study can unite the dichotomy and speed up the process of inhibitor design and development.
Fang
Jianguo
J
Department of Chemistry, Center for Molecular Innovation and Drug Discovery, Chemistry of Life Processes Institute, Northwestern University, Evanston, Illinois 60208-3113, USA.
Ji
Haitao
H
Lawton
Graham R
GR
Xue
Fengtian
F
Roman
Linda J
LJ
Silverman
Richard B
RB
D000818:Animals; D001120:Arginine; D020134:Catalytic Domain; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006639:Histidine; D006801:Humans; D020128:Inhibitory Concentration 50; D007700:Kinetics; D008958:Models, Molecular; D016297:Mutagenesis, Site-Directed; D050505:Mutant Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D052248:Nitric Oxide Synthase Type I / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D051381:Rats; D013379:Substrate Specificity
D004791:Enzyme Inhibitors; D050505:Mutant Proteins; D006639:Histidine; D001120:Arginine; D052248:Nitric Oxide Synthase Type I