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An investigation into the role that tetrahydrobiopterin plays in nitric oxide synthase.

Nitric oxide synthase (NOS), a heme-containing enzyme, converts L-arginine to Lcitrulline and the free radical nitric oxide (NO). NO has gained considerable amount of attention for its role as a neurotransmitter in the brain, a vasodilator in smooth muscles, and a cytotoxic agent that targets tumor cells. The exact mechanism of how NO is formed by NOS is not fully understood. Catalytic activity of NOS requires the substrate Larginine, the cofactor is 6R-5,6,7,8-tetrahydro-biopterin (BH4), calcium/calmodulin complex, oxygen and reductants. NOS contains the internal reductants NADPH and flavins, but without a fully-reduced (tetrahydro) pterin bound like BH4, product is not formed. Oxidized pterins do not bind at all and partially-reduced pterins (dihydro) bind but do not form product. This suggests, but does not prove, that the pterin cofactor provides redox chemistry.

Our studies focus on the exact role BH4 using pterin analogs that are substituted at positions that directly hydrogen bond to the heme in the active site. The synthetically made 4-methoxy-biopterin and 3-methyl-biopterin were obtained from Germany have been successfully reduced to the corresponding tetrahydro form. Dissociation constants of the analogs binding to NOS have been determined to be 15 micromolar and 50 micromolar, respectively, using double reciprocal plot analysis. Future studies include rapid scan stop flow experiments to detect any catalytic intermediates formed when these analogues are bound. A better understanding of the binding and reactivity of pterin analogues will give insight as to exactly how NO is produced in vivo which could lead to therapeutic studies of its regulation.
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Author:McPherson, Alex; Rogers,Amy L.
Publication:Bulletin of the South Carolina Academy of Science
Date:Jan 1, 2005
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