Heme A synthase does not incorporate molecular oxygen into the formyl group of heme A

Biochemistry
Kenneth R BrownEric L Hegg

Abstract

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 (18)O(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 H(2)(18)O, 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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