[Biological and pathophysiological roles of endogenous methylarginines as inhibitors of nitric oxide synthase].
Protein arginine N-methyltransferases (PRMTs) catalyse the methylation of guanidinonitrogen(s) of arginine to produce NG-monomethyl-L-arginine (L-NMMA), asymmetric NG,NG-dimethyl-L-arginine (ADMA) and symmetric NG,NG-dimethyl-L-arginine (SDMA), which are subsequently released into the cytoplasm following proteolysis. Free intracellular L-NMMA and ADMA, but not SDMA, are inhibitors of all three isoforms of nitric oxide synthases (nNOS, eNOS and iNOS). L-NMMA and ADMA, but not SDMA, are actively metabolized by dimethylarginine dimethylaminohydrolase (DDAH) to L-citrulline and methylamine (and dimethylamine). Free methylarginines are detectable in cell cytosol, plasma and tissues. Elevated ADMA has been detected in the plasma of patients or experimental animals with hypercholesterolemia, renal failure, atherosclerosis, hypertension, thrombotic microangiopathy, peripheral arterial occlusive disease and in the regenerated endothelial cells after angioplasty. Moreover, in the non-cardiovascular field, ADMA was increased in the urethral tissue following ischemia and in the plasma of patients with schizophrenia and multiple sclerosis. Altered biosynthesis of NO has been implicated in the pathogenesis of these diseases, and it is possible to consider that the accumulation of endogenous L-NMMA and ADMA underlies the impaired NO generation and increased O2- production. We described herein the biosynthesis, transmembrane transport, metabolic pathway and possible pathophysiological roles of endogenous methylarginines.
Masuda
Hitoshi
H
Department of Urology & Reproductive Medicine, Institute of Biomaterials & Bioengineering, Graduate School, Tokyo Medical & Dental University, Tokyo 101-0062, Japan. hi-masu.uro@tmd.ac.jp
Azuma
Hiroshi
H
D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D019323:omega-N-Methylarginine / Q000378:metabolism / Q000502:physiology*
D019323:omega-N-Methylarginine; C018524:N,N-dimethylarginine; D001120:Arginine; D019001:Nitric Oxide Synthase