Structural insights into the hydrolysis of cellular nitric oxide synthase inhibitors by dimethylarginine dimethylaminohydrolase

Murray-Rust, J., Leiper, J. , McAlister, M., Phelan, J., Tilley, S., Santa Maria, J., Vallance, P. and McDonald, N. (2001) Structural insights into the hydrolysis of cellular nitric oxide synthase inhibitors by dimethylarginine dimethylaminohydrolase. Nature Structural Biology, 8(8), pp. 679-683. (doi:10.1038/90387) (PMID:11473257)

Full text not currently available from Enlighten.

Abstract

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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Leiper, Professor James
Authors: Murray-Rust, J., Leiper, J., McAlister, M., Phelan, J., Tilley, S., Santa Maria, J., Vallance, P., and McDonald, N.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
Journal Name:Nature Structural Biology
Publisher:Nature Publishing Group
ISSN:1072-8368
ISSN (Online):2331-365X

University Staff: Request a correction | Enlighten Editors: Update this record