Oxidative damage to eNOS by tissue peroxynitrite

March 13, 2002

The peroxynitrite anion (ONOO-) is blamed for chemically modifying a variety of proteins and lipid species under conditions of inflammation and oxidative stress. Building on their present studies of the peroxynitrite's effects on the endothelial NO synthase (eNOS), Zou et al. propose a biochemical pathway by which such damage can be propagated in vascular tissue. eNOS and the other NOS's are more or less directly responsible for the formation of this molecule, since they produce two highly reactive species, NO and the superoxide radical (O2·-), which spontaneously combine to form peroxynitrite. In its ordinary role, eNOS consumes molecular oxygen, coupling this redox reaction to the production of NO from arginine. However, the enzyme can also operate in an "uncoupled" mode, where it does not produce NO but simply releases reactive oxygen species, such as peroxide and superoxide. Even in a purified preparation of recombinant eNOS, the combination of coupled and uncoupled catalysis generates NO and superoxide, and therefore yields peroxynitrite. Crucially, Zou et al. find, eNOS itself is highly susceptible to damage by peroxynitrite, which removes a zinc atom that is complexed to both subunits of the normal eNOS homodimer, leaving an enzyme that operates in the uncoupled mode. The structural change thus favors the production of more superoxide and peroxynitrite, which can damage not just eNOS, but also other susceptible enzymes in the endothelium. Zou et al. show that the peroxynitrite-induced loss of zinc from eNOS - and the consequent shift to uncoupled catalysis - is not simply an in vitro process, but that the same pattern of events occurs in cultured endothelial cells exposed to oxidizing levels of glucose, as well as in the tissues of diabetic mice.

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