Institute of Toxicology, Core Unit Proteomics, Hannover Medical School, 30623, Hannover, Germany.
Institute of Toxicology, Core Unit Proteomics, Hannover Medical School, Carl-Neuberg-Strasse 1, 30625, Hannover, Germany.
Cardiovasc Diabetol. 2018 Jan 4;17(1):1. doi: 10.1186/s12933-017-0656-x.
N-Methylation of L-arginine (Arg) residues in certain proteins by protein arginine methyltransferases and subsequent proteolysis yields N-monomethyl-L-arginine (MMA), N,N-dimethyl-L-arginine (asymmetric dimethylarginine, ADMA) and N,N'-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 N-methylated proteins.
精氨酸（Arg）残基的 N-甲基化由蛋白质精氨酸甲基转移酶（protein arginine methyltransferases）完成，随后经蛋白水解得到 N-单甲基-L-精氨酸（N-monomethyl-L-arginine，MMA）、N,N-二甲基-L-精氨酸（不对称二甲基精氨酸，asymmetric dimethylarginine，ADMA）和 N,N'-二甲基-L-精氨酸（对称二甲基精氨酸，symmetric dimethylarginine，SDMA）。生物体内的 MMA、ADMA 和 SDMA 以纳摩尔级别的游离酸形式和大量未知数量的蛋白质残基形式存在。精氨酸：甘氨酸酰胺转移酶（arginine:glycine amidinotransferase，AGAT）催化游离 Arg 和 L-赖氨酸合成 L-同型精氨酸（hArg）。生物体内的 hArg 被认为仅以纳摩尔级别的游离酸形式存在。一氧化氮合酶（nitric oxide synthase，NOS）催化 Arg（高亲和力）和 hArg（低亲和力）转化为一氧化氮（NO），NO 是一种多功能信号分子。MMA、ADMA 和 SDMA 是 NOS 活性的抑制剂（MMA＞ADMA≫SDMA）。在循环中，ADMA 和 SDMA 浓度略有升高，hArg 浓度略有降低，与多种疾病相关，包括糖尿病。然而，这存在矛盾：（1）游离 ADMA 和 SDMA 是内皮型一氧化氮合酶（endothelial nitric oxide synthase，eNOS）的弱抑制剂，eNOS 主要负责心血管系统中与 NO 相关的效应，而游离 hArg 是 eNOS 的不良底物；（2）游离 ADMA、SDMA 和 hArg 与氧化应激无关，氧化应激被认为会诱导与 NO 相关的内皮功能障碍。ADMA/SDMA/hArg 矛盾可以通过以下假设解决：不是游离酸，而是它们的前体蛋白在血管系统中发挥生物学效应，hArg 拮抗 N-甲基化蛋白的作用。
