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J. Biol. Chem., Vol. 283, Issue 6, 3628-3638, February 8, 2008

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Nitrite Reductase Activity of Hemoglobin S (Sickle) Provides Insight into Contributions of Heme Redox Potential Versus Ligand Affinity^*

Rozalina Grubina¹, Swati Basu^¶, Mauro Tiso, Daniel B. Kim-Shapiro^¶32, and Mark T. Gladwin^||34

From the Vascular Medicine Branch, NHLBI, and the ^||Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, Maryland 20892, the Howard Hughes Medical Institute, National Institutes of Health Research Scholars Program, Bethesda, Maryland 20814, and the ^¶Department of Physics, Wake Forest University, Winston-Salem, North Carolina 27109

Hemoglobin A (HbA) is an allosterically regulated nitrite reductase that reduces nitrite to NO under physiological hypoxia. The efficiency of this reaction is modulated by two intrinsic and opposing properties: availability of unliganded ferrous hemes and R-state character of the hemoglobin tetramer. Nitrite is reduced by deoxygenated ferrous hemes, such that heme deoxygenation increases the rate of NO generation. However, heme reactivity with nitrite, represented by its bimolecular rate constant, is greatest when the tetramer is in the R quaternary state. The mechanism underlying the higher reactivity of R-state hemes remains elusive. It can be due to the lower heme redox potential of R-state ferrous hemes or could reflect the high ligand affinity geometry of R-state tetramers that facilitates nitrite binding. We evaluated the nitrite reductase activity of unpolymerized sickle hemoglobin (HbS), whose oxygen affinity and cooperativity profile are equal to those of HbA, but whose heme iron has a lower redox potential. We now report that HbS exhibits allosteric nitrite reductase activity with competing proton and redox Bohr effects. In addition, we found that solution phase HbS reduces nitrite to NO significantly faster than HbA, supporting the thesis that heme electronics (i.e. redox potential) contributes to the high reactivity of R-state deoxy-hemes with nitrite. From a pathophysiological standpoint, under conditions where HbS polymers form, the rate of nitrite reduction is reduced compared with HbA and solution-phase HbS, indicating that HbS polymers reduce nitrite more slowly.

Received for publication, June 26, 2007 , and in revised form, December 3, 2007.

^* This work was supported in part by National Institutes of Health Grants HL58091 and HL078706 (to D. B. K.-S.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Supported by the Division of Intramural Research of the NHLBI, National Institutes of Health.

³ Both authors are listed as co-inventors on an NIH patent application entitled "Use of Nitrite Salts for the Treatment of Cardiovascular Conditions."

² To whom correspondence may be addressed. Tel.: 336-758-4993; Fax: 336-758-6142; E-mail: shapiro{at}wfu.edu.

⁴ Supported by the Division of Intramural Research of the NHLBI, National Institutes of Health. To whom correspondence may be addressed: Bldg. 10, CRC, Rm. 5-5140, 10 Center Dr., Bethesda, MD 20892-1662. Tel.: 301-435-2310; Fax: 301-451-7091; E-mail: mgladwin{at}nih.gov.

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