Hemopexin

Recently, the three-dimensional structure of hemopexin with heme bound has been determined by X-ray crystallography (M. Paoli, H. M. Baker, B. F. Anderson, W. T. Morgan, A. Smith, E. N. Baker, impublished results). Preliminary results show that both domains have the same )ff-propeller fold, as expected from the high homology between the N- and C-domains (25% amino acid identity). The heme molecule, however, is found to be bound in a pocket between the two domains, confined in part by the peptide linker that connects the two domains. This arrangement immediately suggests mechanisms whereby the heme could be released, as a result of domain movements. The two histidine ligands for coordination of the heme-iron are from the linker peptide and from the C-domain, both conserved in all 

5 Role of redox-active metals in the regulation of the metallothionein 

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Hemopexin (binds heme) Retinol-binding protein (binds retinol) Sex hormone-binding globulin (binds testosterone, estradiol) Thyroid-binding globulin (binds T4, T3) Transferrin (transport iron)... 

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. 

Figure 2 Domain structure of the MMPs 92 kDa gelatinase-A (MMP-2), 72 kDa gelatinase-B (MMP-9), the collagenases (MMP-1, -8, and -13), stromelysin-1 (MMP-3) and matrilysin (MMP-7). Matrilysin is the only known MMP that does not have a C-terminal hemopexin-like domain.

Bode W. A helping hand for collagenases the hemopexin-like domain. Structure 1995 3 527-530. 

Binding and Transport of Iron-Porphyrins by Hemopexin WilliamT. Morgan and Ann Smith... 

Liang, O. D., Preissner, K. T., and Chhatwal, G. S. (1997). The hemopexin-type repeats of human vitronectin are recognized by Streptococcus pyogenes. Biochem. Biophys. Res. Commun. 234,445-449. 

A. Heme Transfer to Hemopexin and Direct Antioxidant Effects... 

E. Reduction of Heme-Hemopexin and Binding of Exogenous Ligands... 

C. Working Model of the Hemopexin-Mediated Heme Transport Process... 

Here, the structure and function of hemopexin, the mechanisms of hemopexin-mediated heme transport, and the biological consequences of this specific transport system are reviewed and questions for future research proposed. This is an opportune time for review since recent advances not only provide new viewpoints and directions but also enable new insights to be derived from earlier work. 

Hemopexin was first identified as a heme binding P-globin in elec-trophoretograms of plasma of patients with hemolysis (17-19). The protein is synthesized and secreted by the liver (20-22), and during secretion the signal peptide is removed and the protein is glycosylated (23). Tissue forms of hemopexin are expected due to the presence of mRNA in brain (24), peripheral neurons (25), and neural retina (26), pointing to a function of hemopexin in barrier tissues. 

Although normally present in normal human plasma in abundance ( 0.6 mg/ml, 10 pM) (27-30), concentrations ofhemopexin are sensitive to a variety of pathological conditions. Decreased levels have been noted in chronic and severe hemolytic states (31) and in heme infusion of acute intermittent porphyria patients (32). On the other hand, hemopexin levels increase in the acute-phase response (33-36), and hemopexin has been designated as a type II acute-phase reactant. Plasma hemopexin also increases in certain conditions of muscle breakdown and neuromuscular disease (37). 

The human hemopexin gene has been cloned (38) and is located near the P-globin gene cluster on human chromosome 11 (39). The promoters of the human, rat, and mouse hemopexin genes have been cloned, and the human gene contains a liver specific element (40) and an interleukin-6 responsive element (41), consistent with the positive acute phase response ofhemopexin (33,34). 

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