The Redox Activity of Hemoglobins: From Physiologic Functions to Pathologic Mechanisms

Abstract

Pentacoordinate respiratory hemoproteins such as hemoglobin and myoglobin have evolved to supply cells with oxygen. However, these respiratory heme proteins are also known to function as redox enzymes, reacting with compounds such as nitric oxide and peroxides. The recent discoveries of hexacoordinate hemoglobins in vertebrates and nonsymbiotic plants suggest that the redox activity of globins is inherent to the molecule. The uncontrolled formation of radical species resulting from such redox chemistry on respiratory hemoproteins can lead to oxidative damage and cellular toxicity. In this review, we examine the functions of various globins and the mechanisms by which these globins act as redox enzymes under physiologic conditions. Evidence that redox reactions also occur under disease conditions, leading to pathologic complications, also is examined, focusing on recent discoveries showing that the ferryl oxidation state of these hemoproteins is present in these disease states in vivo. In addition, we review the latest advances in the understanding of globin redox mechanisms and how they might affect cellular signaling pathways and how they might be controlled therapeutically or, in the case of hemoglobin-based blood substitutes, through rational design. Antioxid. Redox Signal. 13, 1087–1123. Introduction More Than Just Oxygen-Binding Proteins Neuroglobin and Cytoglobin: Redox-Active Hemoglobins? Plant Hemoglobins Symbiotic plant hemoglobins Nonsymbiotic plant hemoglobins Other Hemoglobins Truncated bacterial and plant hemoglobins Erythrocruorins The Redox Chemistry of Myoglobin and Hemoglobin in Their Reactions with Ligands and Oxidants Nitric oxide Sulfide Peroxide Hemoglobin redox activity and lipid-oxidation biochemistry Isoprostanes Electrophilic-responsive element Heme-to-Protein Cross-Linked Globins, a Marker for Peroxidatic Activity of Globins Hemoglobin and Myoglobin Redox Activity In Vivo Hemoglobin redox activity under physiologic conditions Hemoglobinopathies, oxidative stress, and malaria Toxicity in the kidney: The redox activity of myoglobin after rhabdomyolysis Toxicity in the brain: The redox activity of hemoglobin after subarachnoid hemorrhage Targets for therapeutic intervention Hemoproteins versus Labile Iron Ferryl Heme Protonation Gates Globin Toxicity The Importance of Tyrosine in the Oxidation of Substrates Hemoglobin and Its Use as an Artificial Blood Substitute The rational design of hemoglobin-based oxygen carriers The redox chemistry of hemoglobin-based oxygen carriers: Inducers of oxidative stress? Conclusions