Kotthaus Jürke, Schade Dennis, Töpker-Lehmann Katrin, Beitz Eric, Clement Bernd
Department of Pharmaceutical Chemistry, Pharmaceutical Institute, Christian-Albrechts-University of Kiel, Gutenbergstr. 76-78, D-24118 Kiel, Germany.
Bioorg Med Chem. 2008 Mar 1;16(5):2305-12. doi: 10.1016/j.bmc.2007.11.066. Epub 2007 Nov 29.
So far N(delta)-methyl-l-arginine (MA) is only detected in yeast cells. Assuming that MA also exists in mammalians we examined possible physiological effects of N(delta)-methylated l-arginine derivatives on the nitric oxide generating system, that is, nitric oxide synthase (NOS), arginase and dimethylarginine dimethylaminohydrolase (DDAH). N(delta)-methyl-l-citrulline (MC) turned out to be a weak non-specific inhibitor of nitric oxide synthases. Moreover, MA is hydroxylated by all human NOS isoforms to N(omega)-hydroxy-N(delta)-methyl-l-arginine (NHAM) but not converted further. This hydroxylated intermediate, however, was detected to be a potent inhibitor of bovine liver arginase with a K(i) of 17.1+/-2.2 microM.
到目前为止，N(δ)-甲基-L-精氨酸（MA）仅在酵母细胞中被检测到。假设MA也存在于哺乳动物中，我们研究了N(δ)-甲基化L-精氨酸衍生物对一氧化氮生成系统，即一氧化氮合酶（NOS）、精氨酸酶和二甲基精氨酸二甲胺水解酶（DDAH）的可能生理作用。结果表明，N(δ)-甲基-L-瓜氨酸（MC）是一氧化氮合酶的一种弱非特异性抑制剂。此外，MA被所有人类NOS同工型羟基化为N(ω)-羟基-N(δ)-甲基-L-精氨酸（NHAM），但不会进一步转化。然而，这种羟基化中间体被检测为牛肝精氨酸酶的有效抑制剂，其抑制常数（K(i)）为17.1±2.2微摩尔。
