Division of Angiology, Department of Internal Medicine III, University Center for Vascular Medicine, Technische Universität Dresden, 01307 Dresden, Germany.
Department of Anaesthesiology and Critical Care Medicine, University Hospital Dresden, Technische Universität Dresden, 01307 Dresden, Germany.
Int J Mol Sci. 2019 Sep 17;20(18):4592. doi: 10.3390/ijms20184592.
Endogenous methylarginines were proposed as cardiovascular risk factors more than two decades ago, however, so far, this knowledge has not led to the development of novel therapeutic approaches. The initial studies were primarily focused on the endogenous inhibitors of nitric oxide synthases asymmetric dimethylarginine (ADMA) and monomethylarginine (MMA) and the main enzyme regulating their clearance dimethylarginine dimethylaminohydrolase 1 (DDAH1). To date, all the screens for DDAH1 activators performed with the purified recombinant DDAH1 enzyme have not yielded any promising hits, which is probably the main reason why interest towards this research field has started to fade. The relative contribution of the second DDAH isoenzyme DDAH2 towards ADMA and MMA clearance is still a matter of controversy. ADMA, MMA and symmetric dimethylarginine (SDMA) are also metabolized by alanine: glyoxylate aminotransferase 2 (AGXT2), however, in addition to methylarginines, this enzyme also has several cardiovascular protective substrates, so the net effect of possible therapeutic targeting of AGXT2 is currently unclear. Recent studies on regulation and functions of the enzymes metabolizing methylarginines have given a second life to this research direction. Our review discusses the latest discoveries and controversies in the field and proposes novel directions for targeting methylarginines in clinical settings.
二十多年前，内源性甲基精氨酸被提出作为心血管风险因素，然而，到目前为止，这方面的知识尚未导致新的治疗方法的发展。最初的研究主要集中在一氧化氮合酶的内源性抑制剂不对称二甲基精氨酸（ADMA）和单甲基精氨酸（MMA）以及调节其清除的主要酶二甲基精氨酸二甲氨基水解酶 1（DDAH1）。迄今为止，用纯化的重组 DDAH1 酶进行的所有 DDAH1 激活剂筛选都没有产生任何有希望的结果，这可能是该研究领域的兴趣开始减弱的主要原因。第二种 DDAH 同工酶 DDAH2 对 ADMA 和 MMA 清除的相对贡献仍然存在争议。ADMA、MMA 和对称二甲基精氨酸（SDMA）也被丙氨酸：乙醛酸氨基转移酶 2（AGXT2）代谢，然而，除了甲基精氨酸外，这种酶还有几种心血管保护底物，因此，可能针对 AGXT2 进行治疗的净效果目前尚不清楚。最近关于代谢甲基精氨酸的酶的调节和功能的研究为这一研究方向赋予了新的生命。我们的综述讨论了该领域的最新发现和争议，并为在临床环境中靶向甲基精氨酸提出了新的方向。
