FIG. 2.

Generation and metabolism of ROS/RNS. O₂^•− is produced by NOXs, the mitochondrial ETC, XO, lipoxygenase, cyclooxygenase, and uncoupled NOS. O₂^•− is converted by SODs to H₂O₂, which, in turn, is reduced to water via the actions of catalase, GPXs, and PRXs. The PRX/TRX and GPX/GSH systems are fueled by NADPH, which is generated by the PPP, IDHs, MEs, and 1C metabolism. Of note, NADPH is also a substrate for the ROS-generating NOXs and NOS. In the presence of reduced transition metals (Fe²⁺ and Cu²⁺), H₂O₂ undergoes spontaneous conversion to reactive OH^• or related metal-associated reactive species. NO^• is produced by coupled NOS. The NOS enzymes utilize NADPH and l-arginine as co-substrates and BH₄ (a product of 1C metabolism) as essential co-factors. Although all NOS isoforms generate NO^•, they can also generate O₂^•− at the expense of NO^• via a process known as uncoupling. The mechanisms underlying the uncoupling process include the formation of monomers, altered Hsp90 binding, and insufficient levels of BH₄ and l-arginine. Importantly, NO^• can be rapidly inactivated via a reaction with O₂^•−, which leads to the formation of the strong oxidant, ONOO⁻. Thus, SODs are the first line of defense against O₂^•−-mediated toxicity. The SODs also participate in cell signaling events via their capacity to regulate levels of ROS (e.g., O₂^•−, H₂O₂) while preserving available NO^•. BH₄, tetrahydrobiopterin; GPX, glutathione peroxidase; H₂O₂, hydrogen peroxide; Hsp, heat-shock protein; NO^•, nitric oxide; NOS, nitric oxide synthase; NOX, NADPH oxidase; O₂^•−, superoxide; OH^•, hydroxyl radical; ONOO⁻, peroxynitrite; PRX, peroxiredoxin; RNS, reactive nitrogen species; SOD, superoxide dismutase; XO, xanthine oxidase. Color images are available online.