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Abstract:

Nitric oxide synthases (NOS) are heme proteins that have a cysteine residue as axial ligand, which generates nitric oxide (NO). The proximal environment, specifically H-bonding between tryptophan (Trp) 178 and thiolate, has been proposed to play a fundamental role in the modulation of NOS activity. We analyzed the molecular basis of this modulation by performing electronic structure calculations on isolated model systems and hybrid quantum-classical computations of the active sites in the protein environment for wild-type and mutant (Trp 178 × Gly) proteins. Our results show that in the ferrous proteins NO exhibits a considerable trans effect. We also showed that in the ferrous (Fe +2 ) mutant NOS the absence of Trp, experimentally associated to a protonated cysteine, weakens the Fe-S bond and yields five coordinate complexes. In the ferric (Fe +3 ) state, the NO dissociation energy is shown to be slightly smaller in the mutant NOS, implying that the Fe +3 -NO complex has a shorter half-life. We found computational evidence suggesting that ferrous NOS is favored in wild-type NOS when compared to the Trp mutant, consistently with the fact that Trp mutants have been shown to accumulate less Fe +2 -NO dead end species. We also found that the heme macrocycle showed a significant distortion in the wild-type protein, due to the presence of the nearby Trp 178. This may also play a role in the subtle tuning of the electronic structure of the heme moiety. © SBIC 2005.

Registro:

Documento: Artículo
Título:Proximal effects in the modulation of nitric oxide synthase reactivity: A QM-MM study
Autor:Fernández, M.L.; Martí, M.A.; Crespo, A.; Estrin, D.A.
Filiación:Departamento de Química Inorgánica, Analítica Y Química Física, INQUIMAE-CONICET, Pabellón II, Buenos Aires, C1428EHA, Argentina
Palabras clave:Density functional theory; Heme proteins; Nitric oxide; NOS; QM-MM; cysteine; heme; iron; macrocyclic compound; nitric oxide; nitric oxide synthase; protein; sulfur; tryptophan; article; calculation; chemical bond; comparative study; electronics; enzyme activity; half life time; modulation; molecular biology; priority journal; quantum chemistry; structure analysis; Binding Sites; Computational Biology; Heme; Hemeproteins; Humans; Hydrogen Bonding; Iron; Models, Molecular; Nitric Oxide Synthase Type III; Tryptophan
Año:2005
Volumen:10
Número:6
Página de inicio:595
Página de fin:604
DOI: http://dx.doi.org/10.1007/s00775-005-0004-6
Título revista:Journal of Biological Inorganic Chemistry
Título revista abreviado:J. Biol. Inorg. Chem.
ISSN:09498257
CODEN:JJBCF
CAS:cysteine, 4371-52-2, 52-89-1, 52-90-4; heme, 14875-96-8; iron, 14093-02-8, 53858-86-9, 7439-89-6; nitric oxide synthase, 125978-95-2; nitric oxide, 10102-43-9; protein, 67254-75-5; sulfur, 13981-57-2, 7704-34-9; tryptophan, 6912-86-3, 73-22-3; Heme, 14875-96-8; Hemeproteins; Iron, 7439-89-6; Nitric Oxide Synthase Type III, EC 1.14.13.39; NOS3 protein, human, EC 1.14.13.39; Tryptophan, 73-22-3
Registro:https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_09498257_v10_n6_p595_Fernandez

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Citas:

---------- APA ----------
Fernández, M.L., Martí, M.A., Crespo, A. & Estrin, D.A. (2005) . Proximal effects in the modulation of nitric oxide synthase reactivity: A QM-MM study. Journal of Biological Inorganic Chemistry, 10(6), 595-604.
http://dx.doi.org/10.1007/s00775-005-0004-6
---------- CHICAGO ----------
Fernández, M.L., Martí, M.A., Crespo, A., Estrin, D.A. "Proximal effects in the modulation of nitric oxide synthase reactivity: A QM-MM study" . Journal of Biological Inorganic Chemistry 10, no. 6 (2005) : 595-604.
http://dx.doi.org/10.1007/s00775-005-0004-6
---------- MLA ----------
Fernández, M.L., Martí, M.A., Crespo, A., Estrin, D.A. "Proximal effects in the modulation of nitric oxide synthase reactivity: A QM-MM study" . Journal of Biological Inorganic Chemistry, vol. 10, no. 6, 2005, pp. 595-604.
http://dx.doi.org/10.1007/s00775-005-0004-6
---------- VANCOUVER ----------
Fernández, M.L., Martí, M.A., Crespo, A., Estrin, D.A. Proximal effects in the modulation of nitric oxide synthase reactivity: A QM-MM study. J. Biol. Inorg. Chem. 2005;10(6):595-604.
http://dx.doi.org/10.1007/s00775-005-0004-6