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. 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.
|Rostovtseva, Tatiana K; Gurnev, Philip A; Protchenko, Olga et al. (2015) ?-Synuclein Shows High Affinity Interaction with Voltage-dependent Anion Channel, Suggesting Mechanisms of Mitochondrial Regulation and Toxicity in Parkinson Disease. J Biol Chem 290:18467-77|
|Cyert, Martha S; Philpott, Caroline C (2013) Regulation of cation balance in Saccharomyces cerevisiae. Genetics 193:677-713|
|Huynh, Chau; Yuan, Xiaojing; Miguel, Danilo C et al. (2012) Heme uptake by Leishmania amazonensis is mediated by the transmembrane protein LHR1. PLoS Pathog 8:e1002795|
|Philpott, Caroline C; Leidgens, Sébastien; Frey, Avery G (2012) Metabolic remodeling in iron-deficient fungi. Biochim Biophys Acta 1823:1509-20|
|Yuan, Xiaojing; Protchenko, Olga; Philpott, Caroline C et al. (2012) Topologically conserved residues direct heme transport in HRG-1-related proteins. J Biol Chem 287:4914-24|
|Boretsky, Yuriy R; Pynyaha, Yuriy V; Boretsky, Volodymyr Y et al. (2011) Identification of the genes affecting the regulation of riboflavin synthesis in the flavinogenic yeast Pichia guilliermondii using insertion mutagenesis. FEMS Yeast Res 11:307-14|