Deuterium isotope effects and product studies for the oxidation of N-omega-allyl-L-arginine and N-omega-allyl-N-omega-hydroxy-L-arginine by neuronal nitric oxide synthase
- Authors
- Hah, Jung-Mi; Roman, Linda J.; Silverman, Richard B.
- Issue Date
- Aug-2000
- Publisher
- PERGAMON-ELSEVIER SCIENCE LTD
- Citation
- BIOORGANIC & MEDICINAL CHEMISTRY, v.8, no.8, pp.1931 - 1936
- Indexed
- SCIE
SCOPUS
- Journal Title
- BIOORGANIC & MEDICINAL CHEMISTRY
- Volume
- 8
- Number
- 8
- Start Page
- 1931
- End Page
- 1936
- URI
- https://scholarworks.bwise.kr/erica/handle/2021.sw.erica/46956
- DOI
- 10.1016/S0968-0896(00)00154-1
- ISSN
- 0968-0896
- Abstract
- The nitric oxide synthases (NOS), which require heme, tetrahydrobiopterin, FMN, FAD, and NADPH, catalyze the O-2-dependent conversion of L-arginine to L-citrulline and nitric oxide. N-omega-Allyl-L-arginine, a mechanism-based inactivator of neuronal NOS, also is a substrate, producing L-arginine, acrolein, and H2O (Zhang, H. Q., Dixon, R. P.; Marletta, R I. A.; Nikolic, D.; Van Breemen, R.; Silverman, R. B. J. Am. Chem. SOC. 1997, 119, 10888). Two possible mechanisms for this turnover an proposed, one initiated by allyl C-I-I bond cleavage and the other by guanidino N-H cleavage, and these mechanisms are investigated with the use of N omega-allyl-L-arginine (1), N-omega-[1,1-H-2(2)]allyl-L-arginine (7), N-omega-allyl-L-hydroxy-L-alginine (2) and N-omega-[1,1-H-2(2)]allyl-N-omega-hydroxy-L-arginine (8) as substrates. Significant isotope effects on the two kinetic parameters, k(cat) and k(cat)/k(m) are observed in case of 1 and 7 during turnover, but not with 2 and 8. No kinetic isotope effects are observed for either compound in their role as inactivators. These results support a mechanism involving initial CH bond cleavage of N-omega-allyl-L-arginine followed by hydroxylation and beakdown to products. (C) 2000 Published by Elsevier Science Ltd.
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