Abstract
Human ferrochelatase, a mitochondrial membrane-associated protein, catalyzes the terminal step of heme biosynthesis by insertion of ferrous iron into protoporphyrin IX. The recently solved x-ray structure of human ferrochelatase identifies a potential binding site for an iron donor protein on the matrix side of the homodimer. Herein we demonstrate Hs holofrataxin to be a high affinity iron binding partner for Hs ferrochelatase that is capable of both delivering iron to ferrochelatase and mediating the terminal step in mitochondrial heme biosynthesis. A general regulatory mechanism for mitochondrial iron metabolism is described that defines frataxin involvement in both heme and iron-sulfur cluster biosyntheses. In essence, the distinct binding affinities of holofrataxin to the target proteins, ferrochelatase (heme synthesis) and ISU (iron-sulfur cluster synthesis), allows discrimination between the two major iron-dependent pathways and facilitates targeted heme biosynthesis following down-regulation of frataxin.
Highlights
Human ferrochelatase, a mitochondrial membrane-associated protein, catalyzes the terminal step of heme biosynthesis by insertion of ferrous iron into protoporphyrin IX
To further characterize potential roles for frataxin as a mitochondrial iron donor, we have investigated the involvement of Hs frataxin in cellular heme biosynthesis as an iron donor to Hs ferrochelatase
We characterize the interaction of human frataxin and ferrochelatase and demonstrate holofrataxin to serve as a potential iron donor to ferrochelatase for insertion into the protoporphyrin ring during heme synthesis
Summary
Recent evidence has pointed to a functional role for frataxin in mitochondrial iron metabolism, including iron-sulfur cluster [1,2,3,4,5] and heme (6 – 8) biosynthesis. Iron release by frataxin appeared to be the rate-limiting step Overall these results correlate well with other published observations concerning a possible role for frataxin in iron-sulfur cluster biosynthesis [2,3,4,5]. We characterize the interaction of human frataxin and ferrochelatase and demonstrate holofrataxin to serve as a potential iron donor to ferrochelatase for insertion into the protoporphyrin ring during heme synthesis
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