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Dihydroorotate Dehydrogenase

III. INTERACTIONS WITH SUBSTRATES, INHIBITORS, ARTIFICIAL ELECTRON ACCEPTORS, AND CYTOCHROME c

Richard W. Miller 1 and Carolyn T. Kerr 1

From the 1 From the New England Institute for Medical Research, Ridgefield, Connecticut 06877

1. Inactivation of dihydroorotate dehydrogenase on reaction with molecular oxygen was observed. The effect is thought to result from the action of highly reactive oxygen intermediates on the catalytic centers of the enzyme. Hydrogen peroxide, the ultimate product of oxygen utilization in this system, was shown to be a less effective inactivator under certain conditions.

2. Ions of heavy metals, including silver, rapidly and reversibly inactivate the enzyme. Sensitivity to, and degree of inhibition by, metal ions were observed to be greater in the presence of sodium orotate than in the absence of this physiological acceptor. Orotate would appear to induce changes in the catalytic state of this nonheme iron flavoprotein.

3. Further evidence for orotate-induced changes of state was obtained with unactivated enzyme, i.e. enzyme having very low activity for orotate reduction. Under certain conditions the substrate appeared to inhibit reduced nicotinamide adenine dinucleotide oxidase activity. Appreciable activity for reduction of orotate was observed only in the presence of sodium ethylenediaminetetraacetate, confirming a close relationship between changes of state and sensitivity to metal ion inactivation.

4. Studies with a class of artificial electron acceptors, the ditetrazolium salts, indicated complex effects of oxygen on rates of diformazan appearance in aqueous media. Under certain conditions oxygen markedly inhibited the reaction while under other experimental conditions no effect or stimulation was observed. Two separate sites of reaction with ditetrazolium salts are proposed to explain these results.

5. Reactions involving another artificial acceptor, potassium ferricyanide, exhibited apparent turnover numbers far exceeding those of the physiological reactions. In addition, the ferrocyanide-ferricyanide oxidation-reduction couple was found to substitute for oxygen as an intermediate electron carrier in the reduction of cytochrome c. Oxygen, therefore, is not an obligatory mediator of this reaction as catalyzed by dihydroorotate dehydrogenase.

Submitted on March 9, 1966


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