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. Although S. cerevisiae does not take up heme in response to iron deprivation, we have determined that this species does have an inducible heme uptake system that is activated under heme deficiency and hypoxic conditions. We performed microarray analysis of strains grown under these conditions, and found that a number of putative transporters are transcriptionally activated. We have identified transporters that, when over expressed, increase heme uptake into yeast. We have also identified a transporter, termed PUG1 (Porphyrin uptake gene 1), that stimulates the uptake of protoporphyrin IX, the immediate precursor of heme, and simultaneously inhibits the utilization of heme. This transporter is transcriptionally activated by oxygen and heme deficiency and is expressed on the plasma membrane of yeast. 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.