Abstract
NG-Methylation of l-arginine (Arg) residues in certain proteins by protein arginine methyltransferases and subsequent proteolysis yields NG-monomethyl-l-arginine (MMA), NG,NG-dimethyl-l-arginine (asymmetric dimethylarginine, ADMA) and NG,N′G-dimethyl-l-arginine (symmetric dimethylarginine, SDMA). Biological MMA, ADMA and SDMA occur as free acids in the nM-range and as residues of proteins of largely unknown quantity. Arginine:glycine amidinotransferase (AGAT) catalyzes the synthesis of L-homoarginine (hArg) from free Arg and l-lysine. Biological hArg is considered to occur exclusively as free acid in the lower µM-range. Nitric oxide synthase (NOS) catalyzes the conversion of Arg (high affinity) and hArg (low affinity) to nitric oxide (NO) which is a pleiotropic signaling molecule. MMA, ADMA and SDMA are inhibitors (MMA > ADMA ≫ SDMA) of NOS activity. Slightly elevated ADMA and SDMA concentrations and slightly reduced hArg concentrations in the circulation are associated with many diseases including diabetes mellitus. Yet, this is paradox: (1) free ADMA and SDMA are weak inhibitors of endothelial NOS (eNOS) which is primarily responsible for NO-related effects in the cardiovascular system, with free hArg being a poor substrate for eNOS; (2) free ADMA, SDMA and hArg are not associated with oxidative stress which is considered to induce NO-related endothelial dysfunction. This ADMA/SDMA/hArg paradox may be solved by the assumption that not the free acids but their precursor proteins exert biological effects in the vasculature, with hArg antagonizing the effects of NG-methylated proteins.
Highlights
The nitric oxide synthase (NOS) family comprises the endothelial NOS, the neuronal NOS and the inducible NOS
Their proteolysis releases the free acids of NG-monomethyll-arginine (MMA), NG,NG-dimethyl-l-arginine, and NG,N′Gdimethyl-l-arginine
A likely reason could be the generalization of the results reported by Vallance et al [3] with respect to the rather very weak inhibitory action of free asymmetric dimethylarginine (ADMA) and their uncritical extension to endothelial NOS (eNOS), and the almost complete neglect of free symmetric dimethylarginine (SDMA) in the subsequent years
Summary
The nitric oxide synthase (NOS) family comprises the endothelial NOS (eNOS), the neuronal NOS (nNOS) and the inducible NOS (iNOS). The observation of the higher cardiorenal significance of SDMA was highly unexpected in the scientific community because free SDMA was generally considered not to be an NOS inhibitor To overcome this contradiction, an alternative mechanism has been proposed, namely the potential of free SDMA and free ADMA to induce oxidative stress which is generally assumed to be a major contributor to cardiovascular disease. Unlike ADMA and SDMA, low circulating and urinary concentrations of free l-hArg were found to be associated with elevated cardiovascular risk, morbidity and mortality. This finding was surprising because l-hArg was considered a nonphysiological and non-proteinogenic amino acid until recently. This examination and our arguments against l-Arg/ NOS-based effects of ADMA, SDMA and hArg in the cardiovascular system are outlined and discussed below in detail
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