Eukaryotic Heme Utilization

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Very little is known about heme transport in eukaryotes and a heme-specific transport uptake systems have not been identified in yeast. Heme is synthesized in mitochondria, yet the cofactor is used in compartments throughout the cell. Heme is highly hydrophobic and is unlikely to be released into the aqueous environment of the cytosol, suggesting that mechanisms exist for the intracellular trafficking of heme. We have designed a genetic screen for the identification of yeast proteins involved in intracellular heme trafficking and are evaluating candidates. Genes identified in this screen suggest that heme moves from the mitochondria to other sites through the vesicular trafficking system. In collaboration with Iqbal Hamza of the University of Maryland, we are functionally characterizing the putative heme transporters of C. elegans by expressing them in yeast. Heme transporters from C. elegans have heme uptake activity when expressed in yeast and mutant forms of heme transporters exhibit loss of function when expressed in yeast. A putative heme transporter from the human pathogen Leishmania amazonensis was identified. We analyzed its heme transport activity in yeast and found evidence that the protein encoded by LHR1 was also a heme importer required for viability and virulence in the pathogen L. amazonensis. We are currently characterizing the heme efflus activity of the putative mitochondrial heme exporter of humans, FLVCR1b.