Autor: Patrick Vallance, Neil Q. McDonald, Judith Murray-Rust, John P. Phelan, James Leiper, Mark Mcalister, Jo Santa Maria, Sarah J. Tilley
Rok vydání: 2001
Předmět:
Zdroj: Nature Structural Biology. 8:679-683
ISSN: 1072-8368
DOI: 10.1038/90387
Popis: Nitric oxide synthase is inhibited by asymmetric NG-methylated derivatives of arginine whose cellular levels are controlled in part by dimethylarginine dimethylaminohydrolase (DDAH, EC 3.5.3.18). 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 2.1.4.1) and arginine deiminase (EC 3.5.3.6), 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.
Databáze: OpenAIRE
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