Reactions of Recombinant Neuronal Nitric Oxide Synthase with Redox Cycling Xenobiotics: A Mechanistic Study
Abstract
:1. Introduction
2. Results
2.1. Steady-State Kinetics and Substrate Specificity of nNOS
2.2. Kinetics of nNOS Oxidation under Multiple Turnover Conditions
3. Discussion
4. Materials and Methods
4.1. Enzymes and Reagents
4.2. Steady-State Kinetic Studies
4.3. Presteady-State Kinetic Studies
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Appendix A
Conditions | E1 (V) | |
---|---|---|
−CAM | +CAM | |
Flavin reductase domain, pH 7.1 [55] | −0.274 (−0.268) | −0.267 (−0.261) |
Holoenzyme, pH 7.0 [54] | −0.220 | −0.220 a |
Flavin reductase domain, pH 7.5 [56] | −0.300 (−0.270) | |
Flavin reductase domain, pH 7.4 [41] | −0.199 (−0.175) | −0.284 (−0.260) |
Flavin reductase domain, pH 7.6 [39] | −0.276 (−0.240) |
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No. | Compound | E17 (V) [32,33] | −CAM | +CAM | ||
---|---|---|---|---|---|---|
kcat (s−1) | kcat/Km (M−1s−1) | kcat (s−1) | kcat/Km (M−1s−1) | |||
Aromatic N-oxides | ||||||
1. | 7-CF3-tirapazamine | −0.345 | 3.98 ± 0.38 | 9.9 ± 1.2 × 103 | 16.3 ± 1.8 | 2.5 ± 0.2 × 104 |
2. | 7-Cl-tirapazamine | −0.400 | 0.84 ± 0.08 | 1.4 ± 0.1 × 104 | 14.8 ± 1.7 | 4.0 ± 0.6 × 105 |
3. | 7-F-tirapazamine | −0.400 | 2.84 ± 0.23 | 1.2 ± 0.1 × 104 | 11.1 ± 1.1 | 1.4 ± 0.1 × 105 |
4. | 3-Amino-1,2,4-benzotriazine-1,4- dioxide (tirapazamine) | −0.456 | 0.69 ± 0.09 | 1.1 ± 0.1 × 103 | 5.22 ± 0.66 | 3.9 ± 0.2 × 104 |
5. | 7-CH3-tirapazamine | −0.474 | 0.60 ± 0.09 | 1.3 ± 0.2 × 103 | ND | ND |
6. | 7-C2H5O-tirapazamine | −0.494 | 0.67 ± 0.09 | 2.2 ± 0.2 × 103 | 2.94 ± 0.71 | 2.6 ± 0.2 × 104 |
Quinones | ||||||
7. | 1,4-Benzoquinone | 0.090 | 12.9 ± 1.5 | 5.1 ± 0.7 × 105 | 61.4 ± 7.2 | 1.3 ± 0.2 × 106 |
8. | 2,6-(CH3)2-1,4-benzoquinone | −0.080 | 6.84 ± 0.42 | 1.4 ± 0.2 × 105 | 55.8 ± 3.4 | 1.0 ± 0.1 × 106 |
9. | 5-OH-1,4-naphthoquinone | −0.090 | 23.3 ± 1.9 | 2.8 ± 0.4 × 106 | 42.2 ± 1.8 | 7.0 ± 0.6 × 106 |
10. | 5,8-(OH)2-1,4-naphthoquinone | −0.110 | 11.5 ± 1.2 | 1.8 ± 0.2 × 106 | 24.7 ± 4.8 | 5.0 ± 0.5 × 107 |
11. | 1,4-Naphthoquinone | −0.150 | 7.98 ± 0.40 | 3.4 ± 0.7 × 105 | 38.2 ± 2.6 | 2.4 ± 0.3 × 106 |
12. | 2-CH3-1,4-naphthoquinone | −0.200 | 8.50 ± 0.80 | 1.6 ± 0.3 × 105 | 37.9 ± 2.5 | 1.3 ± 0.2 × 106 |
13. | (CH3)4-1,4-benzoquinone (duroquinone) | −0.260 | 4.71 ± 0.34 | 8.0 ± 1.0 × 104 | 115.0 ± 7.0 112.2 ± 4.3 a 84.3 ± 5.1 b | 2.1 ± 0.2 × 106 1.2 ± 0.1 × 106 a 1.1 ± 0.1 × 106 b |
14. | 2-OH-1,4-naphthoquinone | −0.410 | 0.39 ± 0.05 | 4.4 ± 0.4 × 103 | 3.11 ± 0.35 | 4.0 ± 0.3 × 104 |
Single electron acceptors | ||||||
15. | Ferricyanide | 0.410 | 30.4 ± 3.5 | 1.2 ± 0.2 × 105 | 102.4 ± 5.9 | 3.3 ± 0.3 × 106 |
16. | Cytochrome c | 0.250 | 9.66 ± 0.35 | 1.9 ± 0.2 × 105 | 104.1 ± 2.2 | 5.3 ± 0.3 × 106 |
17. | Fe(EDTA)− | 0.120 | 7.30 ± 1.30 | 7.0 ± 1.0 × 103 | 11.0 ± 1.2 | 2.8 ± 0.2 × 104 |
18. | Benzylviologen | −0.354 | 6.60 ± 0.40 | 3.4 ± 0.2 × 104 | 23.5 ± 1.4 | 1.7 ± 0.1 × 105 |
Nitroaromatic compounds | ||||||
19. | 2,4,6-Trinitrophenyl-N-methyl- nitramine (tetryl) | −0.191 | ND | ND | 52.0 ± 2.6 | 6.8 ± 0.5 × 106 |
20. | 2,4,6-Trinitrotoluene | −0.253 | ND | ND | 46.4 ± 5.2 | 1.5 ± 0.1 × 105 |
21. | o-Dinitrobenzene | −0.287 | ND | ND | 18.9 ± 3.0 | 8.0 ± 0.7 × 104 |
22. | m-Dinitrobenzene | −0.348 | ND | ND | 10.1 ± 0.9 | 8.9 ± 0.6 × 103 |
23. | p-Nitroacetophenone | −0.355 | ND | ND | 4.67 ± 1.40 | 2.7 ± 0.3 × 104 |
24. | 5-(1-Aziridinyl)-2,4-dinitro- benzamide (CB-1954) | −0.385 | ND | ND | 8.83 ± 0.80 | 2.7 ± 0.2 × 104 |
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Lesanavičius, M.; Boucher, J.-L.; Čėnas, N. Reactions of Recombinant Neuronal Nitric Oxide Synthase with Redox Cycling Xenobiotics: A Mechanistic Study. Int. J. Mol. Sci. 2022, 23, 980. https://doi.org/10.3390/ijms23020980
Lesanavičius M, Boucher J-L, Čėnas N. Reactions of Recombinant Neuronal Nitric Oxide Synthase with Redox Cycling Xenobiotics: A Mechanistic Study. International Journal of Molecular Sciences. 2022; 23(2):980. https://doi.org/10.3390/ijms23020980
Chicago/Turabian StyleLesanavičius, Mindaugas, Jean-Luc Boucher, and Narimantas Čėnas. 2022. "Reactions of Recombinant Neuronal Nitric Oxide Synthase with Redox Cycling Xenobiotics: A Mechanistic Study" International Journal of Molecular Sciences 23, no. 2: 980. https://doi.org/10.3390/ijms23020980