The heme molecule is integral to life. In mammals heme is present in forms a, b, and c. The hemoproteins, cytochrome c and myoglobin, which are of particular interest to the present proposal, contain heme c and heme b, respectively, as their prosthetic moiety. Curiously, virtually nothing is known about the mechanism for the degradation of intact cytochrome c and myoglobin which are essential for metabolic functions of heart. In contrast, substantial evidence exists relating metal ion-toxicity to their effects on the metabolic functions of the heart. For example, a higher degree of mortality due to heart failure is observed in individuals who are exposed to metal ions in their occupations. Approximately a decade ago we defined microsomal heme b oxygenase as a distinct enzyme protein: we described the remarkable capacity of heavy and transition metal ions to increase the activity of the enzyme, and cause a depression in the mitochondrial contents of heme and cytochromes in the heart. Heme oxygenase is rate-limiting in the heme degradative pathway. Recently we have reported on the presence of heme c oxygenase activity in liver mitochondria. We have also observed the acceleration of the degradation rate of intact myoglobin and its conversion to bile pigments in vivo in metal ion-treated animals. However, in vitro neither intact cytochrome c nor intact myoglobin were substrates for heme oxygenase, although the denatured form of myoglobin and peptide-bound heme c served as substrates for the enzyme. Accordingly, we postulate that the catabolism of the hemoproteins in vivo requires an initial processing of the hemoproteins to a form suitable to serve as substrates for heme oxygenase. It is further postulated that the site of the degradation of the heme moiety of cytochrome c is the mitochondrial fraction. The objectives of the proposed research are to expand our knowledge of the heme and hemoprotein degradative processes, and to enhance our understanding of metal ion toxicity.
The specific aims to be investigated are: 1) to isolate and characterize mitochondrial heme oxygenase in the heart and to establish whether the mitochondrial enzyme protein is the same as that of the microsomal source. The regulatory effect of metal ions on the synthesis and the possible translocation of the mitochondrial enzyme will be also investigated; 2) to study the mechanism for the degradation of intact cytochrome c in vivo and the effect of metal ions on the degradative processes; and 3) to investigate further the mechanism for the degradation of intact myoglobin at the cellular level.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
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University of Rochester
School of Medicine & Dentistry
United States
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