Factors that distort the heme structure in Heme-Nitric Oxide/OXygen-Binding (H-NOX) protein domains. A theoretical study

Oxygen binding to the oxygenase domain of reduced endothelial nitric oxide synthase (eNOS) results in two distinct species differing in their Soret and visible absorbance maxima and in their capacity to exchange oxygen by CO. At 7 °C, heme-oxy I (with maxima at 420 and 560 nm) is formed very rapidly (kon≈ 2.5·106m–1·s–1) in the absence of substrate but in the presence of pterin cofactor. It is capable of exchanging oxygen with CO at –30 °C. Heme-oxy II is formed more slowly (kon≈ 3·105m–1·s–1) in the presence of substrate, regardless of the presence of pterin. It is also formed in the absence of both substrate and pterin. In contrast to heme-oxy I, it cannot exchange oxygen with CO at cryogenic temperature. In the presence of arginine, heme-oxy II is characterized by absorbance maxima near 432, 564, and 597 nm. When arginine is replaced byN-hydroxyarginine, and also in the absence of both substrate and pterin, its absorbance maxima are blue-shifted to 428, 560, and 593 nm. Heme-oxy I seems to resemble the ferrous dioxygen complex observed in many hemoproteins, including cytochrome P450. Heme-oxy II, which is the oxygen complex competent for product formation, appears to represent a distinct conformation in which the electronic configuration is essentially locked in the ferric superoxide complex.

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Theoretical study of the reduction of nitric oxide in an A-type flavoprotein

JBIC Journal of Biological Inorganic Chemistry ◽

10.1007/s00775-006-0166-x ◽

2006 ◽

Vol 12 (1) ◽

pp. 79-89 ◽

Cited By ~ 36

Author(s):

L. Mattias Blomberg ◽

Margareta R. A. Blomberg ◽

Per E. M. Siegbahn

Keyword(s):

Nitric Oxide ◽

Theoretical Study

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Experimental and Theoretical Study of Nitric Oxide Formation in Internal Combustion Engines

Combustion Science and Technology ◽

10.1080/00102206908952211 ◽

1970 ◽

Vol 1 (4) ◽

pp. 313-326 ◽

Cited By ~ 496

Author(s):

GEORGE A. LAVOIE ◽

JOHN B. HEYWOOD ◽

JAMES C. KECK

Keyword(s):

Nitric Oxide ◽

Internal Combustion Engines ◽

Theoretical Study ◽

Internal Combustion ◽

Combustion Engines ◽

Oxide Formation ◽

Nitric Oxide Formation

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Role of Nitric Oxide Carried by Hemoglobin in Cardiovascular Physiology

Circulation Research ◽

10.1161/circresaha.119.315626 ◽

2020 ◽

Vol 126 (1) ◽

pp. 129-158 ◽

Cited By ~ 7

Author(s):

Richard T. Premont ◽

James D. Reynolds ◽

Rongli Zhang ◽

Jonathan S. Stamler

Keyword(s):

Nitric Oxide ◽

Blood Flow ◽

Oxygen Delivery ◽

Tissue Oxygenation ◽

Common Factor ◽

Well Being ◽

Therapeutic Interventions ◽

Oxygen Binding ◽

Metabolic Demand ◽

Hypoxic Vasodilation

A continuous supply of oxygen is essential for the survival of multicellular organisms. The understanding of how this supply is regulated in the microvasculature has evolved from viewing erythrocytes (red blood cells [RBCs]) as passive carriers of oxygen to recognizing the complex interplay between Hb (hemoglobin) and oxygen, carbon dioxide, and nitric oxide—the three-gas respiratory cycle—that insures adequate oxygen and nutrient delivery to meet local metabolic demand. In this context, it is blood flow and not blood oxygen content that is the main driver of tissue oxygenation by RBCs. Herein, we review the lines of experimentation that led to this understanding of RBC function; from the foundational understanding of allosteric regulation of oxygen binding in Hb in the stereochemical model of Perutz, to blood flow autoregulation (hypoxic vasodilation governing oxygen delivery) observed by Guyton, to current understanding that centers on S-nitrosylation of Hb (ie, S-nitrosohemoglobin; SNO-Hb) as a purveyor of oxygen-dependent vasodilatory activity. Notably, hypoxic vasodilation is recapitulated by native S-nitrosothiol (SNO)–replete RBCs and by SNO-Hb itself, whereby SNO is released from Hb and RBCs during deoxygenation, in proportion to the degree of Hb deoxygenation, to regulate vessels directly. In addition, we discuss how dysregulation of this system through genetic mutation in Hb or through disease is a common factor in oxygenation pathologies resulting from microcirculatory impairment, including sickle cell disease, ischemic heart disease, and heart failure. We then conclude by identifying potential therapeutic interventions to correct deficits in RBC-mediated vasodilation to improve oxygen delivery—steps toward effective microvasculature-targeted therapies. To the extent that diseases of the heart, lungs, and blood are associated with impaired tissue oxygenation, the development of new therapies based on the three-gas respiratory system have the potential to improve the well-being of millions of patients.

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How Do Heme-Protein Sensors Exclude Oxygen? Lessons Learned from Cytochrome c′, Nostoc puntiforme Heme Nitric Oxide/Oxygen-Binding Domain, and Soluble Guanylyl Cyclase

Antioxidants and Redox Signaling ◽

10.1089/ars.2012.4564 ◽

2012 ◽

Vol 17 (9) ◽

pp. 1246-1263 ◽

Cited By ~ 43

Author(s):

Ah-lim Tsai ◽

Emil Martin ◽

Vladimir Berka ◽

John S. Olson

Keyword(s):

Nitric Oxide ◽

Cytochrome C ◽

Guanylyl Cyclase ◽

Soluble Guanylyl Cyclase ◽

Heme Protein ◽

Binding Domain ◽

Lessons Learned ◽

Oxygen Binding ◽

Protein Sensors

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Changing the paradigm for myoglobin: a novel link between lipids and myoglobin

Journal of Applied Physiology ◽

10.1152/japplphysiol.00973.2013 ◽

2014 ◽

Vol 117 (3) ◽

pp. 307-315 ◽

Cited By ~ 9

Author(s):

Amber E. Schlater ◽

Michael A. De Miranda ◽

Melinda A. Frye ◽

Stephen J. Trumble ◽

Shane B. Kanatous

Keyword(s):

Oxidative Stress ◽

Nitric Oxide ◽

Tissue Sample ◽

Oxidative Stress Marker ◽

Oxygen Binding ◽

High Fat ◽

Western Blots ◽

High Fat Diets ◽

Lipid Supplementation ◽

Fat Diets

Myoglobin (Mb) is an oxygen-binding muscular hemeprotein regulated via Ca2+-signaling pathways involving calcineurin (CN), with Mb increases attributed to hypoxia, exercise, and nitric oxide. Here, we show a link between lipid supplementation and increased Mb in skeletal muscle. C2C12 cells were cultured in normoxia or hypoxia with glucose or 5% lipid. Mb assays revealed that lipid cohorts had higher Mb than control cohorts in both normoxia and hypoxia, whereas Mb Western blots showed lipid cohorts having higher Mb than control cohorts exclusively under hypoxia. Normoxic cells were compared with soleus tissue from normoxic rats fed high-fat diets; whereas tissue sample cohorts showed no difference in CO-binding Mb, fat-fed rats showed increases in total Mb protein (similar to hypoxic cells), suggesting increases in modified Mb. Moreover, Mb increases did not parallel CN increases but did, however, parallel oxidative stress marker augmentation. Addition of antioxidant prevented Mb increases in lipid-supplemented normoxic cells and mitigated Mb increases in lipid-supplemented hypoxic cells, suggesting a pathway for Mb regulation through redox signaling independent of CN.

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