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Research ArticleArticle

Nitric Oxide Synthase Structure and Electron Transfer

Paul R. Ortiz de Montellano, Clinton Nishida, Ignacio Rodriguez-Crespo and Nancy Gerber
Drug Metabolism and Disposition December 1998, 26 (12) 1185-1189;
Paul R. Ortiz de Montellano
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Clinton Nishida
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Ignacio Rodriguez-Crespo
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Nancy Gerber
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Abstract

The nitric oxide synthases (NOS), although unrelated to the cytochromes P450 in terms of sequence, exhibit spectroscopic and catalytic properties strongly reminiscent of those of the P450 system. One important difference is the requirement of the NOS enzymes for tetrahydrobiopterin. The biopterin cofactor is shown by chemical studies to bind close to pyrrole ring D of the prosthetic heme group, a position confirmed recently for inducible NOS and endothelial NOS by crystal structures. The only plausible role so far for the tetrahydrobiopterin is as a transient electron donor for the activation of molecular oxygen. NADPH-derived electrons are provided to the heme by the NOS flavin domain, but the biopterin may be required to provide an electron at a faster rate than that supported by the flavin groups. Chimeras in which the reductase domains of the isoforms have been exchanged indicate that the overall rate of catalytic turnover is directly governed by the ability of the flavin domain to deliver electrons. Electron transfer from the flavin to the heme domain, and within the flavin and heme domains, is thus a critical determinant of the catalytic turnover of NOS.

Footnotes

  • Send reprint requests to: Dr. Paul R. Ortiz de Montellano, School of Pharmacy, University of California, San Francisco, CA 94143-0446. e-mail: ortiz{at}cgl.ucsf.edu

  • The work in the author’s laboratory was supported by National Institutes of Health grant GM25515.

  • Abbreviations used are::
    NOS
    nitric oxide synthase
    CaM
    Ca2+-dependent calmodulin
    P450
    cytochrome P450
    l-Arg
    l-arginine
    FAD
    flavin adenine dinucleotide
    FMN
    flavin mononucleotide
    H4B
    5,6,7,8-tetrahydrobiopterin
    nNOS
    neuronal NOS
    iNOS
    inducible NOS
    eNOS
    endothelial NOS
    heme
    iron protoporphyrin IX regardless of iron coordination and oxidation state
    PDZ
    domains of ∼80 amino acids found in structural proteins of the cytoskeleton and in enzymes that associate with the cytoskeleton, and therefore thought to be involved in protein-protein interaction (also called GLGF repeats or DHRs)
    E/N
    chimera consisting of the eNOS heme and CaM-binding domains and the nNOS flavin domain
    I/N
    chimera consisting of the iNOS heme and CaM-binding domains and the nNOS flavin domain
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition
Vol. 26, Issue 12
1 Dec 1998
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Research ArticleArticle

Nitric Oxide Synthase Structure and Electron Transfer

Paul R. Ortiz de Montellano, Clinton Nishida, Ignacio Rodriguez-Crespo and Nancy Gerber
Drug Metabolism and Disposition December 1, 1998, 26 (12) 1185-1189;

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Research ArticleArticle

Nitric Oxide Synthase Structure and Electron Transfer

Paul R. Ortiz de Montellano, Clinton Nishida, Ignacio Rodriguez-Crespo and Nancy Gerber
Drug Metabolism and Disposition December 1, 1998, 26 (12) 1185-1189;
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