Nitrite Reductase Activity of Sol-Gel-encapsulated Deoxyhemoglobin

Roche, Camille J.; Dantsker, David; Samuni, Uri; Friedman, Joel M.

doi:10.1074/jbc.m603914200

Cited by 39 publications

(47 citation statements)

References 72 publications

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“…The rate is at least an order of magnitude faster when the deoxygenated ferrous Hb tetramer has the R (relaxed) quaternary structure (83,145,151). For HbA, the T (tense, low ligand binding affinity) …”

Section: Rbcs Nitric Oxide and Vascular Homeostasismentioning

confidence: 99%

HbE/β-Thalassemia and Oxidative Stress: The Key to Pathophysiological Mechanisms and Novel Therapeutics

Hirsch

Sibmooh

Fucharoen

et al. 2017

Antioxidants & Redox Signaling

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Significance: Oxidative stress and generation of free radicals are fundamental in initiating pathophysiological mechanisms leading to an inflammatory cascade resulting in high rates of morbidity and death from many inherited point mutation-derived hemoglobinopathies. Hemoglobin (Hb)E is the most common point mutation worldwide. The b E -globin gene is found in greatest frequency in Southeast Asia, including Thailand, Malaysia, Indonesia, Vietnam, Cambodia, and Laos. With the wave of worldwide migration, it is entering the gene pool of diverse populations with greater consequences than expected. Critical Issues: While HbE by itself presents as a mild anemia and a single gene for b-thalassemia is not serious, it remains unexplained why HbE/b-thalassemia (HbE/b-thal) is a grave disease with high morbidity and mortality. Patients often exhibit defective physical development, severe chronic anemia, and often die of cardiovascular disease and severe infections. Recent Advances: This article presents an overview of HbE/b-thal disease with an emphasis on new findings pointing to pathophysiological mechanisms derived from and initiated by the dysfunctional property of HbE as a reduced nitrite reductase concomitant with excess a-chains exacerbating unstable HbE, leading to a combination of nitric oxide imbalance, oxidative stress, and proinflammatory events. Future Directions: Additionally, we present new therapeutic strategies that are based on the emerging molecular-level understanding of the pathophysiology of this and other hemoglobinopathies. These strategies are designed to short-circuit the inflammatory cascade leading to devastating chronic morbidity and fatal consequences. Antioxid. Redox Signal. 26,[794][795][796][797][798][799][800][801][802][803][804][805][806][807][808][809][810][811][812][813]

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Section: Rbcs Nitric Oxide and Vascular Homeostasismentioning

confidence: 99%

HbE/β-Thalassemia and Oxidative Stress: The Key to Pathophysiological Mechanisms and Novel Therapeutics

Hirsch

Sibmooh

Fucharoen

et al. 2017

Antioxidants & Redox Signaling

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“…It is now well accepted that the allosterically regulated reduction of nitrite by Hb generates nitric oxide (NO) (5,6). Whether this NO produced can escape the RBC and signal in a physiologically relevant manner remains controversial.…”

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Globin X is a six-coordinate globin that reduces nitrite to nitric oxide in fish red blood cells

Cortí

Xue

Tejero

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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The discovery of novel globins in diverse organisms has stimulated intense interest in their evolved function, beyond oxygen binding. Globin X (GbX) is a protein found in fish, amphibians, and reptiles that diverged from a common ancestor of mammalian hemoglobins and myoglobins. Like mammalian neuroglobin, GbX was first designated as a neuronal globin in fish and exhibits six-coordinate heme geometry, suggesting a role in intracellular electron transfer reactions rather than oxygen binding. Here, we report that GbX to our knowledge is the first six-coordinate globin and the first globin protein apart from hemoglobin, found in vertebrate RBCs. GbX is present in fish erythrocytes and exhibits a nitrite reduction rate up to 200-fold faster than human hemoglobin and up to 50-fold higher than neuroglobin or cytoglobin. Deoxygenated GbX reduces nitrite to form nitric oxide (NO) and potently inhibits platelet activation in vitro, to a greater extent than hemoglobin. Fish RBCs also reduce nitrite to NO and inhibit platelet activation to a greater extent than human RBCs, whereas GbX knockdown inhibits this nitrite-dependent NO signaling. The description of a novel, sixcoordinate globin in RBCs with dominant electron transfer and nitrite reduction functionality provides new insights into the evolved signaling properties of ancestral heme-globins.nitrite | nitric oxide | blood | RBC | platelet

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“…This reaction has been implicated in nitrite-and deoxy-Hb-dependent vasodilation in vivo (5, 10 -12) and in vitro (5, 13), as well as in nitrite-mediated cytoprotection following ischemia-reperfusion injury (14 -17). An analogous reaction of nitrite with deoxymyoglobin (deoxy-Mb) has been associated with the regulation of cardiomyocyte respiration during physiological and pathological hypoxia (18,19).In an anaerobic environment nitrite is reduced to NO as deoxy-Hb is oxidized to met-Hb (Equation 1) (6,20). NO generated in this reaction can then be bound by other ferrous deoxy-hemes to form iron-nitrosyl-Hb (Equation 2) (21).…”

mentioning

confidence: 99%

“…In an anaerobic environment nitrite is reduced to NO as deoxy-Hb is oxidized to met-Hb (Equation 1) (6,20). NO generated in this reaction can then be bound by other ferrous deoxy-hemes to form iron-nitrosyl-Hb (Equation 2) (21).…”

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confidence: 99%

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

Grubina

Basu

Tiso

et al. 2008

Journal of Biological Chemistry

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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.The various redox reactions catalyzed by ferrous hemes of the heme-globins (primarily hemoglobin and myoglobin) have interested scientists for over 150 years (1). In 1901, while studying the mechanism of meat curing, John Haldane described the ability of nitrite to oxidize hemoglobin (Hb) 5 to methemoglobin (met-Hb) and generate iron-nitrosyl-hemoglobin (iron-nitrosyl-Hb) in sections of meat not exposed to air (2), although he was most likely observing the analogous reaction with myoglobin (Mb). The reaction of nitrite with deoxyhemoglobin (deoxy-Hb) was further characterized by Brooks in 1937 (3) and by Doyle and colleagues in 1981 (4). Recent work has demonstrated that deoxy-Hb can effectively catalyze the reduction of nitrite to NO along physiological oxygen and pH gradients (5-9). This reaction has been implicated in nitrite-and deoxy-Hb-dependent vasodilation in vivo (5, 10 -12) and in vitro (5, 13), as well as in nitrite-mediated cytoprotection following ischemia-reperfusion injury (14 -17). An analogous reaction of nitrite with deoxymyoglobin (deoxy-Mb) has been associated with the regulation of cardiomyocyte respiration during physiological and pathological hypoxia (18,19).In an anaerobic environment nitrite is reduced to NO as deoxy-Hb is oxidized to met-Hb (Equation 1) (6,20). NO generated in this reaction can then be bound by other ferrous deoxy-hemes to form iron-nitrosyl-Hb (Equation 2) (21).Importantly, this reaction is a...

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Nitrite Reductase Activity of Sol-Gel-encapsulated Deoxyhemoglobin

Cited by 39 publications

References 72 publications

HbE/β-Thalassemia and Oxidative Stress: The Key to Pathophysiological Mechanisms and Novel Therapeutics

HbE/β-Thalassemia and Oxidative Stress: The Key to Pathophysiological Mechanisms and Novel Therapeutics

Globin X is a six-coordinate globin that reduces nitrite to nitric oxide in fish red blood cells

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

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