Human Neuroglobin Functions as a Redox-regulated Nitrite Reductase (original) (raw)
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Globin X is a six-coordinate globin that reduces nitrite to nitric oxide in fish red blood cells
Proceedings of the National Academy of Sciences of the United States of America, 2016
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 n...
Antioxidants & Redox Signaling, 2003
The role of nitric oxide (NO) in cellular physiology and signaling has been an important aspect in biomedical science over the last decade. As NO is a small uncharged radical, the chemistry of NO within the redox environment of the cell dictates the majority of its biological effects. The mechanisms that have received the most attention from a biological perspective involve reactions with oxygen and superoxide, despite the rich literature of metal-NO chemistry. However, NO and its related species participate in important chemistry with metalloproteins. In addition to the well known direct interactions of NO with heme proteins such as soluble guanylate cyclase and oxyhemoglobin, there is much important, but often underappreciated, chemistry between other nitrogen oxides and heme/metal proteins. Here the basic chemistry of nitrosylation and the interactions of NO and other nitrogen oxides with metal-oxo species such as found in peroxidases and monoxygenases are discussed. Antioxid. Redox Signal. 5, 307-317.
Invertebrate hemoglobins and nitric oxide: How heme pocket structure controls reactivity
Journal of Inorganic Biochemistry, 2005
Hemoglobins (Hbs), generally defined as 5 or 6 coordinate heme proteins whose primary function is oxygen transport, are now recognized to occur in virtually all phyla of living organisms. Historically, study of their function focused on oxygen as a reversibly bound ligand of the ferrous form of the protein. Other diatomic ligands like carbon monoxide and nitric oxide were considered ''non-physiological'' but useful probes of structure-function relationships in Hbs. This investigatory landscape changed dramatically in the 1980s when nitric oxide was discovered to activate a heme protein, cyclic guanylate cyclase. Later, its activation was likened to PerutzÕ description of HbÕs allosteric properties being triggered by a ligand-dependent ''out-of-plane/into-plane'' movement of the heme iron. In 1996, a functional role for nitric oxide in human and mammalian Hbs was demonstrated and since that time, the interest in NO as a physiologically relevant Hb ligand has greatly increased. Concomitantly, non-oxygen binding properties of Hbs have challenged the view that Hbs arose for their oxygen storage and transport properties. In this focused review we discuss some invertebrate HbsÕ functionally significant reactions with nitric oxide and how strategic positioning of a few residues in the heme pocket plays an large role in the interplay of diatomic ligands to ferrous and ferric heme iron in these proteins.
Nitric Oxide, Invertebrates and Hemoglobin1
American Zoologist, 2001
SYNOPSIS. Rich redox chemistry of the diatomic NO gives this molecule the functional flexibility to interact with both metal and non-metal components of biological molecules. This important biological signaling and allosteric control has become evident in such varied applications as brain/nervous system function; immune response; growth and development; behavior; and gas transport. Many of the basic discoveries linking NO to biological systems have arisen from structure-function relationships in hemoglobin. For example, by analogy with hemoglobin, Lou Ignarro, in a now-classic paper on NO, proposed that the activation of soluble guanylate cyclase occurs via a NO-driven planar shift in the enzyme's heme iron . Many other proteins involved in NO biology are heme proteins where NO coordination plays an essential function. In this regard, we may view hemoglobin as a microcosm of NO biology.
Cell Metabolism, 2006
Eukaryotic cells respond to low-oxygen concentrations by upregulating hypoxic nuclear genes (hypoxic signaling). Although it has been shown previously that the mitochondrial respiratory chain is required for hypoxic signaling, its underlying role in this process has been unclear. Here, we find that yeast and rat liver mitochondria produce nitric oxide (NO) at dissolved oxygen concentrations below 20 mM. This NO production is nitrite (NO 2 2 ) dependent, requires an electron donor, and is carried out by cytochrome c oxidase in a pH-dependent fashion. Mitochondrial NO production in yeast is influenced by the YHb flavohemoglobin NO oxidoreductase, stimulates expression of the hypoxic nuclear gene CYC7, and is accompanied by an increase in protein tyrosine nitration. These findings demonstrate an alternative role for the mitochondrial respiratory chain under hypoxic or anoxic conditions and suggest that mitochondrially produced NO is involved in hypoxic signaling, possibly via a pathway that involves protein tyrosine nitration.
Journal of Biological Chemistry, 2011
) remains an enigma in terms of its contributions to red blood cell (RBC) pathophysiological mechanisms; for example, EE individuals exhibit a mild chronic anemia, and HbE/-thalassemia individuals show a range of clinical manifestations, including high morbidity and death, often resulting from cardiac dysfunction.The purpose of this study was to determine and evaluate structural and functional consequences of the HbE mutation that might account for the pathophysiology. Functional studies indicate minimal allosteric consequence to both oxygen and carbon monoxide binding properties of the ferrous derivatives of HbE. In contrast, redoxsensitive reactions are clearly impacted as seen in the following: 1) the ϳ2.5 times decrease in the rate at which HbE catalyzes nitrite reduction to nitric oxide (NO) relative to HbA, and 2) the accelerated rate of reduction of aquometHbE by L-cysteine (L-Cys). Sol-gel encapsulation studies imply a shift toward a higher redox potential for both the T and R HbE structures that can explain the origin of the reduced nitrite reductase activity of deoxyHbE and the accelerated rate of reduction of aquometHbE by cysteine. Deoxy-and CO HbE crystal structures (derived from crystals grown at or near physiological pH) show loss of hydrogen bonds in the microenvironment of Lys-26 and no significant tertiary conformational perturbations at the allosteric transition sites in the R and T states. Together, these data suggest a model in which the HbE mutation, as a consequence of a relative change in redox properties, decreases the overall rate of Hb-mediated production of bioactive NO.
Ascaris haemoglobin is a nitric oxide-activated 'deoxygenase
Nature, 1999
The parasitic nematode Ascaris lumbricoides infects one billion people worldwide. Its perienteric fluid contains an octameric haemoglobin that binds oxygen nearly 25,000 times more tightly than does human haemoglobin. Despite numerous investigations, the biological function of this molecule has remained elusive. The distal haem pocket contains a metal, oxygen and thiol, all of which are known to be reactive with nitric oxide. Here we show that Ascaris haemoglobin enzymatically consumes oxygen in a reaction driven by nitric oxide, thus keeping the perienteric fluid hypoxic. The mechanism of this reaction involves unprecedented chemistry of a haem group, a thiol and nitric oxide. We propose that Ascaris haemoglobin functions as a 'deoxygenase', using nitric oxide to detoxify oxygen. The structural and functional adaptations of Ascaris haemoglobin suggest that the molecular evolution of haemoglobin can be rationalized by its nitric oxide related functions.