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Blood, 1 October 2008, Vol. 112, No. 7, pp. 2636-2647. Prepublished online as a Blood First Edition Paper on July 2, 2008; DOI 10.1182/blood-2008-01-115261. This Article Full Text (PDF) All Versions of this Article: blood-2008-01-115261v1 112/7/2636    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Gladwin, M. T Articles by Kim-Shapiro, D. B. Search for Related Content PubMed PubMed Citation Articles by Gladwin, M. T Articles by Kim-Shapiro, D. B. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted January 29, 2008 Accepted June 16, 2008 The functional nitrite reductase activity of the heme-globins Mark T Gladwin* and Daniel B. Kim-Shapiro Pulmonary and Vascular Medicine Branch, NHLBI, NIH, Bethesda, MD, United States Department of Physics, Wake Forest University, Winston-Salem, NC, United States * Corresponding author; email: mgladwin{at}nih.gov. Hemoglobin and myoglobin are among the most extensively studied proteins in human history and nitrite one of the most studied small molecules. During the last decade, multiple physiological studies have surprisingly revealed that nitrite represents a biological reservoir of NO that can regulate hypoxic vasodilation, cellular respiration, and signaling. These studies suggest a vital role for deoxyhemoglobin- and deoxymyoglobin-dependent nitrite reduction in these processes. A biophysical and chemical analysis of the nitrite-deoxyhemoglobin reaction has revealed unexpected chemistries between nitrite and deoxyhemoglobin that may contribute to and facilitate hypoxic NO generation and signaling. The first is that hemoglobin is an allosterically regulated nitrite reductase, such that oxygen binding increases the rate of nitrite conversion to NO, a process termed R-state catalysis. The second chemical property is oxidative denitrosylation, a process by which the NO formed in the deoxyhemoglobin-nitrite reaction that binds to other deoxyhemes can be released due to heme oxidation, releasing free NO. Thirdly, the reaction undergoes a nitrite reductase/anhydrase redox cycle that catalyzes the anaerobic conversion of two molecules of nitrite into dinitrogen trioxide (N2O3), an uncharged molecule that can be exported from the erythrocyte. We will review these allosteric reactions of nitrite with the heme-globins in the context of historical studies of nitrite and hemoglobin chemistry, and attempt to place this novel functionality in the biological framework of hypoxic signaling in blood and the heart. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: F. B. Jensen The dual roles of red blood cells in tissue oxygen delivery: oxygen carriers and regulators of local blood flow J. Exp. Biol., November 1, 2009; 212(21): 3387 - 3393. [Abstract] [Full Text] [PDF] B. H. Shaz, C. J. Dente, R. S. Harris, J. B. MacLeod, and C. D. Hillyer Transfusion Management of Trauma Patients Anesth. Analg., June 1, 2009; 108(6): 1760 - 1768. [Abstract] [Full Text] [PDF] A. J. Webb, A. B. Milsom, K. S. Rathod, W. L. Chu, S. Qureshi, M. J. Lovell, F. M.J. Lecomte, D. Perrett, C. Raimondo, E. Khoshbin, et al. Mechanisms Underlying Erythrocyte and Endothelial Nitrite Reduction to Nitric Oxide in Hypoxia: Role for Xanthine Oxidoreductase and Endothelial Nitric Oxide Synthase Circ. Res., October 24, 2008; 103(9): 957 - 964. [Abstract] [Full Text] [PDF]

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