Hemoglobin and heme scavenging

Abstract

Release of hemoglobin into plasma is a physiological phenomenon associated with intravascular hemolysis. In plasma, stable haptoglobin‐hemoglobin complexes are formed and these are subsequently delivered to the reticulo‐endothelial system by CD163 receptor‐mediated endocytosis. Heme arising from the degradation of hemoglobin, myoglobin, and of enzymes with heme prosthetic groups could be delivered in plasma. Albumin, haptoglobin, hemopexin, and high and low density lipoproteins cooperate to trap the plasma heme, thereby ensuring its complete clearance. Then hemopexin releases the heme into hepatic parenchymal cells only after internalization of the hemopexin‐heme complex by CD91 receptor‐mediated endocytosis. Moreover, α1‐microglobulin contributes to heme degradation by a still unknown mechanism, with the concomitant formation of heterogeneous yellow‐brown kynurenine‐derived chromophores which are very tightly bound to amino acid residues close to the rim of the lipocalin pocket. During hemoglobin synthesis, the erythroid α‐chain hemoglobin‐stabilizing protein specifically binds free α‐hemoglobin subunits limiting the free protein toxicity. Although highly toxic because capable of catalyzing free radical formation, heme is also a major and readily available source of iron for pathogenic organisms. Gram‐negative bacteria pick up the heme‐bound iron through the secretion of a hemophore that takes up either free heme or heme bound to heme‐proteins and transports it to a specific receptor, which, in turn, releases the heme and hence iron into the bacterium. Here, hemoglobin and heme trapping mechanisms are summarized. IUBMB Life, 57: 749‐759, 2005

Evidence for pH-dependent multiple conformers in iron(II) heme–human serum albumin: spectroscopic and kinetic investigation of carbon monoxide binding

“…Furthermore, this behavior, which underlies the occurrence of multiple conformations of iron(II) heme-HSA, may have great impact on the function of heme-HSA as a metabolite and drug transporter, since this proton-linked modulation is reflected in its capability of interacting with molecules circulating in the bloodstream, as previously demonstrated [3,8,20,22,[29][30][31][32]. Therefore, HSA, not only acting as a heme carrier but also displaying transient heme-based properties, represents a case for ''chronosteric effects'' [62], which opens the scenario toward the possibility of a time-and metabolite-dependent multiplicity of roles for HSA.…”

“…In addition, the growing importance of the diatomic ligand CO as a gas transducer involved in the signaling related to reactive oxygen species [60] renders these kinetic investigations of physiopathological relevance. Thus, the role played by heme-HSA in the detoxification process is significantly enhanced by the fact that the amount of heme-HSA increases significantly under pathological conditions [9,10,61,62] owing to the function of HSA as a heme scavenger from HDL and LDL, impairing their oxidation [8,48,49].…”

“…Among others, HSA appears (1) to be an important determinant of the pharmacokinetic behavior of many drugs, (2) to account for most of the antioxidant capacity of human serum, and (3) to display enzymatic properties [1][2][3][4][5][6][7][8][9][10][11].…”

“…At pH [ 8.0 and in the absence of ligands, HSA exhibits the basic form, which is characterized by a high affinity for some ligands (e.g., heme). Ligands that bind with the highest affinity to one of the conformational states may allosterically modulate the HSA transition [3,8,20,22,[29][30][31][32].…”

“…Heme binding confers on HSA globin-like spectroscopic and reactivity properties [11,42,44,45]; in addition, HSA-heme has been reported to facilitate scavenging of reactive nitrogen species [46,47]. Furthermore, since the rate of heme transfer from HDL and LDL to HSA and hemoproteins is faster than the heme-induced lipoprotein oxidation [8,48,49], the formation of HSA-heme represents a protective event, which prevents the formation of oxidized HDL and LDL, which are the most oxidatively intolerant plasma components. Afterwards, heme transits from HSA to hemopexin, which releases it into hepatic parenchymal cells after internalization of the hemopexinheme complex by CD91-receptor-mediated endocytosis.…”