Hemopexin heme-binding site

Fig. 12. Schematic views of bis-histidyl ferri-, ferro-, and CO-ferro-heme-hemopexin. Unlike myoglobin with one open distal site, heme bound to hemopexin is coordinated to two strong field ligands, either of which a priori may be displaced by CO. This may well produce coupled changes in protein conformation like the Perutz mechanism for 02-binding by hemoglobin (143). The environment of heme bound to hemopexin and to the N-domain may be influenced by changes in the interactions of porphyrin-ring orbitals with those of aromatic residues in the heme binding site upon reduction and subsequent CO binding.

However, this explanation is not sufficient to accoimt for the bipha-sic CD spectrum of human ferri-protoheme—hemopexin (with 2,4-vinyl substituents), as well as the much weaker human CO-ferro-heme-hemopexin bisignate signal compared to the rabbit congener (139), and hence other factors must be involved. Several potential effectors exist (a) exciton coupling (b) the conformers produced by a 180° rotation about the a- and y-meso-carbon axis and consequent nonisometric interactions of the as5unmetric 2,4- and 9,10-substituents (c) the aromatic tryptophan residues near the heme binding site (s) and (d) two independent binding modes or sites. 

If both MT-1 and HO-1 mRNA induction by heme-hemopexin involves a copper-redox enzyme in both heme transport (and consequent induction of HO-1 mRNA) and the signaling pathway for MT-1 expression, a plausible working model can be formulated by analogy with aspects of the yeast iron uptake processes and with redox reactions in transport (Figure 5-6). First, the ferric heme-iron bound to hemopexin can act as an electron acceptor, and reduction is proposed to be required for heme release. The ferrous heme and oxygen are substrates for an oxidase, possibly NADH-dependent, in the system for heme transport. Like ferrous iron, ferrous heme is more water soluble than ferric heme and thus more suitable as a transport intermediate between the heme-binding site on hemopexin and the next protein in the overall uptake process. The hemopexin system would also include a copper-redox protein in which the copper electrons would be available to produce Cu(I), either as the copper oxidase or for Cu(I) transport across the plasma membrane to cytosolic copper carrier proteins for incorporation into copper-requiring proteins [145]. The copper requirement for iron transport in yeast is detectable only under low levels of extracellular copper as occur in the serum-free experimental conditions often used. 

Fig. 8. Crystal structure of heme-hemopexin. The crystal structure of the rabbit mesoheme-hemopexin complex (PDB accession number IQHU) (11) showed heme to be bound in a relatively exposed site between the N- and C-domains with one axial His ligand being contributed by the hinge or linking region between the domains and the other by the C-domain. Also noteworthy is the disposition of the heme with its propionate residues pointing inward and neutralized by positive charges in the binding site.

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