Abstract
Nitric oxide synthases (NOSs) are a family of bioptero-flavoproteins that convert L-arginine to equimolar quantities of nitric oxide (NO) and L-citrulline. The catalytic mechanism for this reaction is complex, involving electron transfer within NOS from transiently bound NADPH, through flavins in the C-terminal reductase domain, to heme in an N-terminal oxygenase domain — electron transfer is triggered by calmodulin binding to NOS (1). During catalysis, arginine occupies the active site on the oxygenase domain and undergoes two successive heme-dependent monoxygenation reactions, with Nω-hydroxyarginine formed as an isolatable intermediate (2). Tetrahydrobiopterin (BH4) is an essential NOS cofactor (3,4), however its precise role in catalysis has not been established. Notably, one molecule of BH4 is bound in the oxygenase domain of each NOS monomer comprising the functional NOS homodimer. Recent crystal structures have revealed that BH4 binds tightly at the dimer interface of NOSs and makes multiple hydrogen bonds, including interaction with a heme propionate (5,6).
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Jones, C.L., Vásquez-Vivar, J., Kalyanaraman, B., Griscavage-Ennis, J.M., Gross, S.S. (2002). The Redox Status of Bound Pterin Cofactor Determines Whether eNOS Produces NO or Superoxide Anion: [3H]-BH4 Binding Studies Provide Insights into Vascular Pathophysiology. In: Milstien, S., Kapatos, G., Levine, R.A., Shane, B. (eds) Chemistry and Biology of Pteridines and Folates. Springer, Boston, MA. https://doi.org/10.1007/978-1-4615-0945-5_45
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DOI: https://doi.org/10.1007/978-1-4615-0945-5_45
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