title: Covalent bonding of the prosthetic heme to protein: a potential mechanism for the suicide inactivation or activation of hemoproteins.
abstract: In this perspective we have described a newly characterized pathway for the metabolism of the prosthetic heme of cytochrome P-450, which results in the formation of protein-bound adducts. This reaction occurs when the cytochrome P-450 metabolizes a variety of xenobiotics as well as endogenous compounds such as hydrogen peroxide and lipid hydroperoxides. It also takes place during the reactions catalyzed by other hemoproteins, such as myoglobin and hemoglobin. In the case of the reaction of ferrous myoglobin with BrCCl3, under single-turnover conditions, an intact heme moiety becomes covalently bound to an active-site amino acid. This covalently altered protein has significantly enhanced reductive activity compared to that of native myoglobin, as demonstrated by its rapid reduction of molecular oxygen and CCl4. It also is more rapidly proteolyzed than myoglobin. These findings may have relevance to the P-450 cytochromes in which suicide inactivation, destruction of the heme prosthetic group, and loss of the protein is observed. The activation of hemoproteins to heme-protein adducts may also have toxicological significance, perhaps in oxygen reperfusion injury in the myocardium as well as other tissues by enhancing the production of oxygen-derived radicals from molecular oxygen and lipid hydroperoxides. Clearly, further research in the characterization of heme-protein adducts is necessary before their importance in protein turnover and oxygen-induced injury can be determined.
authors.affiliation: Laboratory of Chemical Pharmacology, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland 20892.
authors.forename: Y
authors.initials: Y
authors.lastname: Osawa
authors.forename: L R
authors.initials: LR
authors.lastname: Pohl
mesh_terms: D000818:Animals; D001711:Biotransformation; D006418:Heme / Q000378:metabolism*; D006420:Hemeproteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D011485:Protein Binding
chemical_list: D006420:Hemeproteins; D006418:Heme