Biological significance of endogenous methylarginines that inhibit nitric oxide synthases

The guanidino-methylated arginine analogue NG monomethyl-L-arginine (L-NMMA ) has been the standard nitric oxide synthase inhibitor used to evaluate th e role of the L-arginine:nitric oxide pathway. However, L-NMMA and other me thylated arginine residues are also synthesised in vivo by the action of a family of enzymes known as protein arginine methyltransferases. Proteolysis of proteins containing methylated arginine residues releases free methylar ginine residues into the cytosol from where they may pass out of the cell i nto plasma. Of the three known methylarginine residues produced in mammals only asymmetrically methylated forms (L-NMMA and asymmetric dimethylarginin e (ADMA)) but not symmetrically methylated arginine (symmetric dimethylargi nine (SDMA)) inhibit nitric oxide synthase (NOS). We and others have propos ed that endogenously produced asymmetrically methylated arginines may modul ate NO production and that the accumulation of these residues in disease st ares may contribute to pathology. The activity of the enzyme dimethylargini ne dimethylaminohydrolase that metabolises asymmetric methylarginines may b e of critical importance in affecting NO pathways in health or disease. (C) 1999 Published by Elsevier Science B.V. All rights reserved.