Department of Pharmaceutical and Medicinal Chemistry, Pharmaceutical Institute, Christian-Albrechts-University of Kiel, Germany.
Biochem J. 2011 Jan 15;433(2):383-91. doi: 10.1042/BJ20100960.
NOSs (nitric oxide synthases) catalyse the oxidation of L-arginine to L-citrulline and nitric oxide via the intermediate NOHA (N(ω)-hydroxy-L-arginine). This intermediate is rapidly converted further, but to a small extent can also be liberated from the active site of NOSs and act as a transportable precursor of nitric oxide or potent physiological inhibitor of arginases. Thus its formation is of enormous importance for the nitric-oxide-generating system. It has also been shown that NOHA is reduced by microsomes and mitochondria to L-arginine. In the present study, we show for the first time that both human isoforms of the newly identified mARC (mitochondrial amidoxime reducing component) enhance the rate of reduction of NOHA, in the presence of NADH cytochrome b₅ reductase and cytochrome b₅, by more than 500-fold. Consequently, these results provide the first hints that mARC might be involved in mitochondrial NOHA reduction and could be of physiological significance in affecting endogenous nitric oxide levels. Possibly, this reduction represents another regulative mechanism in the complex regulation of nitric oxide biosynthesis, considering a mitochondrial NOS has been identified. Moreover, this reduction is not restricted to NOHA since the analogous arginase inhibitor NHAM (N(ω)-hydroxy-N(δ)-methyl-L-arginine) is also reduced by this system.
NOSs（一氧化氮合酶）通过中间产物 NOHA（N(ω)-羟基-L-精氨酸）将 L-精氨酸氧化为 L-瓜氨酸和一氧化氮。这种中间产物会进一步快速转化，但在较小程度上也可以从 NOSs 的活性部位释放出来，作为一氧化氮的可运输前体或精氨酸酶的有效生理抑制剂。因此，它的形成对一氧化氮生成系统至关重要。已经表明，NOHA 可被微粒体和线粒体还原为 L-精氨酸。在本研究中，我们首次表明，新鉴定的 mARC（线粒体酰胺肟还原成分）的两种人同工型，在 NADH 细胞色素 b₅ 还原酶和细胞色素 b₅ 的存在下，可将 NOHA 的还原速率提高 500 多倍。因此，这些结果首次提示 mARC 可能参与线粒体 NOHA 的还原，并且可能对影响内源性一氧化氮水平具有生理意义。可能，考虑到已经鉴定出一种线粒体 NOS，这种还原代表了一氧化氮生物合成复杂调节中的另一种调节机制。此外，这种还原不仅限于 NOHA，因为类似的精氨酸酶抑制剂 NHAM（N(ω)-羟基-N(δ)-甲基-L-精氨酸）也可被该系统还原。
