Grand Larceny: Oxidant corrupts protein by filching crucial atom (Oxidative damage; Cardiovascular disease)
Authors: Leslie Mitch 
Published: August 2003

A new study reveals how oxidants undermine an enzyme that helps keep our blood vessels open and clear of clots. These molecular vandals steal an atom of zinc that helps hold the protein together--not only harming the enzyme in the process but also stimulating the production of more of the cell-wrecking chemicals.

By gnawing on proteins and other molecules, oxidants drive heart disease, diabetes, and aging--or so the theory goes (see
"The Two Faces of Oxygen"
). These hungry molecules, such as superoxide and peroxynitrite, are spawned in the normal course of metabolism. How they could wreak so much destruction is an enigma, considering that only 1 in 1000 to 1 in 10,000 amino acids in a cell show signs of oxidative wounds, says Jay Heinecke of Washington University in St. Louis, Missouri, an authority on these baneful molecules.

Zou and colleagues uncovered the effects of oxidants on one of the body's key enzymes, nitric oxide synthase, which comprises two identical halves coupled by a bridge containing zinc and sulfur. True to its name, nitric oxide synthase makes nitric oxide, a versatile and vital signaling molecule that opens blood vessels and inhibits clot formation.

The researchers exposed nitric oxide synthase to peroxynitrite and tracked the enzyme's response. Even small amounts of peroxynitrite broke the protein in half by swiping zinc from the bridge. The same changes occurred when the researchers treated the enzyme with a molecule that locks up zinc, confirming that the parting of the protein resulted from removing the metal. What's more, cells bathed in abnormally large amounts of glucose and cells from diabetic mice showed the same breakup of nitric oxide synthase--which suggests that damage to the enzyme might contribute to diabetes.

Broken nitric oxide synthase doesn't simply fail to produce nitric oxide. Oxidation brings out the enzyme's alter ego, which instead makes superoxide. This promiscuous oxidant can react with nitric oxide to produce yet more peroxynitrite--setting off a runaway process of peroxynitrite formation. Although previous work had suggested that nitric oxide synthase might spawn peroxynitrite, this study is the first to clarify the mechanism and to show how sensitive the enzyme is, even to low concentrations of the oxidant.

Both consequences of oxidation might compromise health, says biochemist Ming-Hui Zou of Boston University School of Medicine. Reduced amounts of nitric oxide narrow blood vessels and spur clotting, which worsen cardiovascular disease. Peroxynitrite also attacks a molecule that prevents constriction of blood vessels, which might explain why the arteries of diabetics expand reluctantly, Zou adds.

According to Heinecke, the results also back a nontraditional view of how oxidants wreak havoc. The conventional notion--that their attack cripples proteins--is hard to square with the rarity of oxidants in the body's cells. A more plausible idea, says Heinecke, is that oxidants pervert proteins instead of wrecking them: "You are damaging a protein in a way that produces a gain in function. It's doing something bad instead of something good."

--Mitch Leslie

M.-H. Zou, C. Shi, R. A. Cohen, Oxidation of the zinc-thiolate complex and uncoupling of endothelial nitric oxide synthase by peroxynitrite.
J. Clin. Invest.
109
, 817-826 (2002).
[Abstract]
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