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.
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Acknowledgements
This work was initiated and funded in part by a British Heart Foundation Programme Grant to P.V., and by the BBSRC through the Bloomsbury Centre for Structural Biology. We thank ESRF and SRS synchrotron sources for use of data collection facilities, and P. Driscoll, D. Selwood and P. Murray-Rust for helpful discussions.
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Murray-Rust, J., Leiper, J., McAlister, M. et al. Structural insights into the hydrolysis of cellular nitric oxide synthase inhibitors by dimethylarginine dimethylaminohydrolase. Nat Struct Mol Biol 8, 679–683 (2001). https://doi.org/10.1038/90387
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DOI: https://doi.org/10.1038/90387
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