Reduction of Nω-hydroxy-L-arginine by the mitochondrial amidoxime reducing component (mARC)

Juerke Kotthaus , Bettina Wahl , Antje Havemeyer , Joscha Kotthaus , Dennis Schade , Dieter Garbe-Schönberg , Ralf Mendel , Florian Bittner , Bernd Clement (1)

1 Department of Pharmaceutical and Medicinal Chemistry

Nitric oxide synthases (NOSs) catalyse the oxidation of L-arginine to L-citrulline and nitric oxide via the intermediate Nω-hydroxy-L-arginine (NOHA). 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. Meanwhile, it has been shown that NOHA is reduced by microsomes and mitochondria to L-arginine. In this study, we show for the first time that both human isoforms of the newly identified mitochondrial amidoxime reducing component (mARC) enhance reduction-rates of NOHA in the presence of NADH cytochrome b5 reductase and cytochrome b5 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 NO biosynthesis considering the existence of a recently identified mitochondrial NOS. Moreover, this reduction is not restricted to NOHA since the analogous arginase inhibitor Nω-hydroxy-Nδ-methyl-L‑arginine (NHAM) is reduced as well.

Mots clés: Life Sciences

Juerke Kotthaus, Bettina Wahl, Antje Havemeyer, Joscha Kotthaus, Dennis Schade, et al.. Reduction of Nω-hydroxy-L-arginine by the mitochondrial amidoxime reducing component (mARC). Biochemical Journal, 2010, 433 (2), pp.383-391. ⟨10.1042/BJ20100960⟩. ⟨hal-00549895⟩