Uncoupling of the eNOS reaction This figure demonstrates the three vulnerable arms of the plasma membrane bound eNOS reaction responsible for the production of the omnipotent endothelial nitric oxide. Oxygen reacts with the eNOS enzyme in which the essential BH4 cofactor has coupled NAD(P)H with L-arginine to be converted to eNO and L-citrulline. If uncoupled due to oxidative – redox stress with the essential BH4 cofactor now in the BH2 or BH3 oxidized state the reaction will become one of superoxide production adding to the oxidative – redox stress within the endothelial microenvironment. The healthy endothelium is a net producer of eNO, whereas, the dysfunctional endothelium becomes a net producer of superoxide. It is in this situation that the stabilization of the essential BH4 cofactor (preventing oxidation to BH4) by adequate supplementation of folate becomes so very important.