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J Biol Chem, Vol. 275, Issue 19, 14070-14076, May 12, 2000

Cu²⁺ and Zn²⁺ Inhibit Nitric-oxide Synthase through an Interaction with the Reductase Domain^*

Jason M. Perry, Yunde Zhao^§, and Michael A. Marletta^§¶

From the  Division of Medicinal Chemistry, College of Pharmacy, ^§ Department of Biological Chemistry, School of Medicine, and the ^¶ Howard Hughes Medical Institute, University of Michigan, Ann Arbor, Michigan 48109-0606

Cu²⁺ and Zn²⁺ inhibit all of the NADPH-dependent reactions catalyzed by neuronal nitric-oxide synthase (nNOS) including ferricytochrome c reduction, NADPH oxidation, and citrulline formation. Cu²⁺ and Zn²⁺ also inhibit ferricytochrome c reduction by the independent reductase domain. Zn²⁺ affects all activities of the full-length nNOS and the reductase domain to the same extent (estimated IC₅₀ values from 9 to 31 µM), suggesting Zn²⁺ occupation of a single site in the reductase domain. Citrulline formation and NADPH oxidation by the full-length nNOS and ferricytochrome c reduction by the reductase domain are affected similarly by Cu²⁺, with estimated IC₅₀ values ranging from 6 to 33 µM. However, Cu²⁺ inhibits ferricytochrome c reduction by the full-length nNOS 2 orders of magnitude more potently, with an estimated IC₅₀ value of 0.12 µM. These data suggest the possibility that Cu²⁺ may interact with nNOS at two sites, one composed exclusively of the reductase domain (which is perhaps also involved in Zn²⁺-mediated inhibition), and another that includes components of both domains. Occupation of the second (higher affinity) site could then promote the selective inhibition of ferricytochrome c reduction in full-length nNOS. Neither the inhibition by Cu²⁺ nor that by Zn²⁺ is dependent on calmodulin.

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