Heme-albumin

If bound first by albumin, heme circulates until it is transferred to hemopexin (52). In vitro in the absence of hemopexin, nonspecific cellular uptake of heme by diffusion is facile (55), but as expected, the presence of hemopexin greatly slows uptake (54), since receptor-mediated uptake is necessarily slower and of lower capacity than diffusion-limited uptake. There is currently no evidence that either receptors for albumin or membrane transporters for heme, like those in prokaryotes, are present in the plasma membrane of mammalian cells, although such transport proteins may be present in the membranes of organelles. 

Tsuchida E, Sou K, Nakagawa A et al (2009) Artificial oxygen carriers, hemoglobin vesicles and albumin-hemes, based on bioconjugate chemistry. Bioconjug Chem 20 1419-1440. 

Biliverdin is an early product of catabohsm and on reduction yields bilirubin. The latter is transported by albumin from peripheral tissues to the hver, where it is taken up by hepatocytes. The iron of heme and the amino acids of globin are conserved and reutilized. 

Certain other plasma proteins bind heme but not hemoglobin. Hemopexin is a Pj-globuhn that binds free heme. Albumin wiU bind some metheme (ferric heme) to form methemalbumin, which then ttansfets the metheme to hemopexin. 

Fig. 1. Overview of intravascular heme catabolism. Hemoglobin, myoglobin, and other heme proteins are released into the circulation upon cellular destruction, and the heme moiety is oxidized by O2 to the ferric form (e.g., methemoglobin and metmyoglobin). Haptoglobin can bind a substantial amount of hemoglobin, but is readily depleted. Ferric heme dissociates from globin and can be bound by albumin or more avidly by hemopexin. Hemopexin removes heme from the circulation by a receptor-mediated transport mechanism, and once inside the ceU heme is transported to heme oxygenase for catabolism.

Heme dissociates from methemoglobin or metmyoglobin in the circulation and can be boimd by hemopexin or albumin, a heme binding plasma protein of lower avidity than hemopexin (49). It is important that the heme be controlled, since this amphipathic, oxidatively active compound can nonspecifically associate with membrane lipids or lipoproteins and cause oxidative damage of vital biomolecules, including DNA (50, 51). 

A dynamic system of heme binding exists in the bloodstream, and to function in heme transport hemopexin must be able to (a) obtain heme from methemoglobin (released by hemolysis) and metmyoglobin (introduced by trauma) (b) compete with serum albumin for heme in the... 

Adding heme to human serum or to a mixture of 70 human albumin 1 hemopexin showed that heme is rapidly bound by hemopexin, whereas heme transfer from a heme-albumin complex (treated to remove loosely bound heme) is much slower (52) and requires 24 hours to complete. This is in accord with the existence of one strong (K 10 nM)... 

In patients clearance of intravenous heme is rapid until hemopexin levels are depleted (148), and lack of interaction with hemopexin may explain the higher clinical efficacy of heme-arginate compared with hemin itself (149, 150). In intact animals, i.v. heme causes rapid association of hemopexin but not albumin with the liver (47, 63, 68), and heme uptake from heme-albumin complexes into isolated rat hepato-cytes occurs via diffusion of heme released from its loose complex with BSA (137). Moreover, unlike uptake from heme-hemopexin, free heme uptake by cells occurred even at 4°C, as expected for nonspecific membrane association and in total disagreement with a membrane-receptor-mediated or active transport uptake process. 

Some have considered uptake of heme from heme-albumin a receptor-mediated process (54, 151), but dissociation of heme from its weak complex with albumin is ignored. Thus, apparent saturation at higher heme-BSA levels is not necessarily due to saturation of receptor but is more likely due to lower concentrations of free heme. The lower capacity of hemopexin-mediated heme transport compared with diffusion of free heme is expected since there is a finite number of receptors per cell a transport protein s job is to target a ligand, not to maximize the amount transported. Further, relevant comparisons must be made at short times on the order of minutes, not hours. 

Biophysical characterization showed that a single HRP II protein bound 17 molecules of heme [35]. In an in vitro heme polymerization assay, HRP II promoted the synthesis of hemozoin, while controls, such as the proteins bovine serum albumin and lysozyme or the homopeptides polyhistidine, polylysine, and polyasparagine, did not. FT-IR analysis of the reaction product showed the characteristic vibrations of hemozoin. The polymerization activity had a pH maximum near 4.0, which dropped off precipitously near the pKa of histidine. The heme polymerization... 

For example, heme in myoglobin hemoglobin b For example, bilirubin in albumin... 

Albumin also acts as a transport medium for a variety of substances. It is the principal, if not the only, means of transport for free bilirubin (breakdown product of heme) and free fatty acids. It also binds calcium ions, hematin, steroids, thyroxine, and various drugs and dyes. 

In one of the reports from this laboratory, we reported that an artificial non-heme iron protein synthesized from serum albumin displays... 

Fig. 13. Absorption spectra of artificial non-heme iron protein (61). Curve A serum albumin treated with 2-mercaptoethanol curve B serum albumin treated with ferrous ammonium sulfate curve C synthesized non-heme iron protein from serum albumin, treated with both 2-mercaptoethanol and ferrous ammonium sulfate...

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