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- W2912293750 abstract "The mammalian inducible nitric oxide synthase (iNOS) catalyzes the production of nitric oxide (NO) in a two-step monooxygenation of L-arginine (L-Arg) to NO and L-citrulline via the intermediate Nω-hydroxy-L-arginine (NOHA). The reaction starts with the formation of a ternary complex consisting of the enzyme, an O2 ligand bound to the heme iron and the L-Arg substrate residing close to the heme-bound ligand. We have blocked the enzymatic turnover by replacing O2 by carbon monoxide (CO), because it resembles O2 in size and heme binding properties, and then studied CO binding to the iNOS oxygenase domain, iNOSoxy, by using flash photolysis. The P420 and P450 forms of the enzyme, assigned to a protonated and unprotonated proximal cysteine, through which the heme is anchored to the protein, show markedly different CO rebinding properties. Only very few CO ligands can escape from P420. They rebind very slowly, suggesting that P420 has a widely open distal pocket that admits water. CO rebinding to the P450 form strongly depends on the presence of the substrate L-Arg, the intermediate Nω-hydroxy-L-arginine and also the cofactor tetrahydrobiopterin. After adding these small molecules to the enzyme solution, the CO kinetics change slowly over hours. This process can be described as a relaxation from a fast rebinding, metastable P450 species to a slowly rebinding, thermodynamically stable P450 species, which we associate with the enzymatically active form. Our results allow us to determine kinetic parameters of L-Arg binding to ferrous deoxy iNOS protein, the L-Arg dissociation rate coefficient,= 15.4 ± 0.4 s−1, the bimolecular L-Arg association rate coefficient, = 1153 ± 71 mM−1s−1, and by taking the ratio of the two values, the equilibrium dissociation coefficient of L-Arg and ferrous iNOSoxy, KD = 13.4 ± 0.9 μM." @default.
- W2912293750 created "2019-02-21" @default.
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- W2912293750 date "2019-02-01" @default.
- W2912293750 modified "2023-09-30" @default.
- W2912293750 title "A Kinetic Study of Ligand Binding and Conformational Changes in Inducible Nitric Oxide Synthase" @default.
- W2912293750 doi "https://doi.org/10.1016/j.bpj.2018.11.399" @default.
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