Article abstract
Nature Chemical Biology 3, 785 - 794 (2007)
Published online: 4 November 2007 | doi:10.1038/nchembio.2007.46
Catalytic generation of N2O3 by the concerted nitrite reductase and anhydrase activity of hemoglobin
Swati Basu1,11, Rozalina Grubina2,3,11, Jinming Huang4, Jeanet Conradie5,6, Zhi Huang2, Anne Jeffers7, Alice Jiang1, Xiaojun He1, Ivan Azarov1, Ryan Seibert1, Atul Mehta1, Rakesh Patel8, Stephen Bruce King4, Neil Hogg9, Abhik Ghosh5, Mark T Gladwin2,10 & Daniel B Kim-Shapiro1,7
Abstract
Nitrite reacts with deoxyhemoglobin to form nitric oxide (NO) and methemoglobin. Though this reaction is experimentally associated with NO generation and vasodilation, kinetic analysis suggests that NO should not be able to escape inactivation in the erythrocyte. We have discovered that products of the nitrite-hemoglobin reaction generate dinitrogen trioxide (N2O3) via a novel reaction of NO and nitrite-bound methemoglobin. The oxygen-bound form of nitrite-methemoglobin shows a degree of ferrous nitrogen dioxide (Fe(II)-NO2
) character, so it may rapidly react with NO to form N2O3. N2O3 partitions in lipid, homolyzes to NO and readily nitrosates thiols, all of which are common pathways for NO escape from the erythrocyte. These results reveal a fundamental heme globin– and nitrite-catalyzed chemical reaction pathway to N2O3, NO and S-nitrosothiol that could form the basis of in vivo nitrite-dependent signaling. Because the reaction redox-cycles (that is, regenerates ferrous heme) and the nitrite-methemoglobin intermediate is not observable by electron paramagnetic resonance spectroscopy, this reaction has been 'invisible' to experimentalists over the last 100 years.
- Department of Physics, Wake Forest University, 1834 Wake Forest Road, Winston-Salem, North Carolina 27109, USA.
- Vascular Medicine Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, 10 Center Drive, MSC 1454, Bethesda, Maryland 20892, USA.
- Howard Hughes Medical Institute–National Institutes of Health Research Scholars Program, 1 Cloister Court, Bethesda, Maryland 20814, USA.
- Department of Chemistry, Wake Forest University, 1834 Wake Forest Road, Winston-Salem, North Carolina 27109, USA.
- Department of Chemistry and Center for Theoretical and Computational Chemistry, University of Tromsø, N-9037 Tromsø, Norway.
- Chemistry Department, University of the Free State, Nelson Mandela Street, Bloemfontein 9301, South Africa.
- Virginia Tech–Wake Forest University School of Biomedical Engineering and Sciences, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, North Carolina 27157, USA.
- Department of Pathology, University of Alabama, 901 19th Street South, BMR-2, Room 302, Birmingham, Alabama 35294, USA.
- Department of Biophysics, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, Wisconsin 53226, USA.
- Critical Care Medicine Department, Clinical Center, National Institutes of Health, 10 Center Drive, MSC 1454, Bethesda, Maryland 20892, USA.
- These authors contributed equally to this work.
Correspondence to: Mark T Gladwin2,10 e-mail: shapiro@wfu.edu
Correspondence to: Daniel B Kim-Shapiro1,7 e-mail: mgladwin@nih.gov
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