Site and mechanism of uncoupling of nitric-oxide synthase: Uncoupling by monomerization and other misconceptions

Publication date: 1 August 2019Source: Nitric Oxide, Volume 89Author(s): Verena Gebhart, Katja Reiß, Alexander Kollau, Bernd Mayer, Antonius C.F. GorrenAbstractNitric oxide synthase (NOS) catalyzes the transformation of l-arginine, molecular oxygen (O2), and NADPH-derived electrons to nitric oxide (NO) and l-citrulline. Under some conditions, however, NOS catalyzes the reduction of O2 to superoxide (O2−) instead, a phenomenon that is generally referred to as uncoupling. In principle, both the heme in the oxygenase domain and the flavins in the reductase domain could catalyze O2− formation. In the former case the oxyferrous (Fe(II)O2) complex that is formed as an intermediate during catalysis would dissociate to heme and O2−; in the latter case the reduced flavins would reduce O2 to O2−. The NOS cofactor tetrahydrobiopterin (BH4) is indispensable for coupled catalysis. In the case of uncoupling at the heme this is explained by the essential role of BH4 as an electron donor to the oxyferrous complex; in the case of uncoupling at the flavins it is assumed that the absence of BH4 results in NOS monomerization, with the monomers incapable to sustain NO synthesis but still able to support uncoupled catalysis. In spite of little supporting evidence, uncoupling at the reductase after NOS monomerization appears to be the predominant hypothesis at present. To set the record straight we extended prior studies by determining under which conditions uncoupling of the neuronal and ...

Source: Nitric Oxide - April 30, 2019 Category: Chemistry Source Type: research