Murray-Rust, J; Leiper, JM; McAlister, M; Phelan, J; Tilley, S; Santa Maria, J; ... McDonald, N; + view all Murray-Rust, J; Leiper, JM; McAlister, M; Phelan, J; Tilley, S; Santa Maria, J; Vallance, P; McDonald, N; - view fewer (2001) Structural insights into the hydrolysis of cellular nitric oxide synthase inhibitors by dimethylarginine dimethylaminohydrolase. Nature Structural and Molecular Biology , 8 (8) 679 - 683. 10.1038/90387.
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Nitric oxide synthase is inhibited by asymmetric NG-methylated derivatives of arginine whose cellular levels are controlled in part by dimethylarginine dimethylaminohydrolase (DDAH, EC 126.96.36.199). Levels of asymmetric NG,NG-dimethylarginine (ADMA) are known to correlate with certain disease states. Here, the first structure of a DDAH shows an unexpected similarity to arginine:glycine amidinotransferase (EC 188.8.131.52) and arginine deiminase (EC 184.108.40.206), thus defining a superfamily of arginine-modifying enzymes. The identification of a Cys- His-Glu catalytic triad and the structures of a Cys to Ser point mutant bound to both substrate and product suggest a reaction mechanism. Comparison of the ADMA-DDAH and arginine-amidinotransferase complexes reveals a dramatic rotation of the substrate that effectively maintains the orientation of the scissile bond of the substrate with respect to the catalytic residues. The DDAH structure will form a basis for the rational design of selective inhibitors, which are of potential use in modulating NO synthase activity in pathological settings
|Title:||Structural insights into the hydrolysis of cellular nitric oxide synthase inhibitors by dimethylarginine dimethylaminohydrolase|
|Additional information:||UI - 21366085 LA - eng RN - 0 (Enzyme Inhibitors) RN - 0 (Ligands) RN - 372-75-8 (Citrulline) RN - EC 220.127.116.11 (Nitric-Oxide Synthase) RN - EC 3. (Hydrolases) RN - EC 18.104.22.168 (dimethylargininase) PT - Journal Article DA - 20010726 IS - 1072-8368 SB - IM CY - United States|
|Keywords:||activity, Amino Acid Sequence, Amino Acid Substitution, antagonists & inhibitors, Arginine, asymmetric, Binding Sites, BOND, Catalysis, catalytic, Cellular, chemistry, Citrulline, comparison, COMPLEX, COMPLEXES, CORRELATE, Crystallography, X-Ray, DERIVATIVES, design, Dimerization, disease, EC, enzyme, Enzyme Inhibitors, Enzymes, Form, genetics, Hydrogen Bonding, Hydrolases, Hydrolysis, IDENTIFICATION, IM, INHIBITOR, INHIBITORS, INSIGHT, INSIGHTS, LA, LEVEL, LIGAND, ligands, MECHANISM, metabolism, Models, Molecular, Molecular Sequence Data, Mutant, nitric oxide, nitric oxide synthase, NITRIC-OXIDE, Nitric-Oxide Synthase, Orientation, OXIDE, pharmacology, Point Mutation, product, Protein Structure, Quaternary, Protein Structure, Tertiary, RATIONAL DESIGN, Rotation, Sequence Alignment, Setting, SETTINGS, STATE, STATES, structural, Structure, SUBSTRATE, Substrate Specificity, Support, Non-U.S.Gov't, SYNTHASE, united, United States, UNITED-STATES, Use|
|UCL classification:||UCL > School of Life and Medical Sciences > Faculty of Medical Sciences > Medicine (Division of)|
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