Journal
BIOCHEMISTRY
Volume 43, Issue 27, Pages 8616-8624Publisher
AMER CHEMICAL SOC
DOI: 10.1021/bi049056m
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- NIGMS NIH HHS [GM66236] Funding Source: Medline
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Heme A is an obligatory cofactor in all eukaryotic and many prokaryotic cytochrome c oxidases. The final step in heme A biosynthesis requires the oxidation of the C8 methyl substituent on pyrrole ring D to an aldehyde, a reaction catalyzed by heme A synthase. To effect this transformation, heme A synthase is proposed to utilize a heme B cofactor, oxidizing the substrate via successive monooxygenase reactions. Consistent with this hypothesis, the activity of heme A synthase is found to be strictly dependent on molecular oxygen. Surprisingly, when cells expressing heme A synthase were incubated with O-18(2), no significant incorporation of label was observed in heme A, the C8 alcohol intermediate, or the C8 overoxidized byproduct. Conversely, when the cells were grown in (H2O)-O-18, partial labeling was observed at every heme oxygen position. These results suggest that the oxygen on the heme A aldehyde is derived from water. Although our data do not allow us to exclude the possibility of exchange with water inside of the cell, the results seem to question a mechanism utilizing successive monooxygenase reactions and support instead a mechanism of heme O oxidation via electron transfer.
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