Heme biosynthesis is an essential process in erythroid and non-erythroid cells. Porphyria cutanea tarda (PCT), a defect in step 5 of the heme biosynthetic pathway, represents the most common form of porphyria in humans. PCT is due reduced specific activity uroporphyrinogen decarboxylase (URO- D), and results in a massive accumulation of the intermediate, uroporphyrin. We have shown that an ABC-type transporter is responsible for moving uroporphyrin into the vacuole in yeast. We will identify the mammalian transporter through targeted proteomics and complementation in yeast. We will confirm the transporter identity by knocking down the candidate in cells and looking for porphyrin localization. We will also define the method used by cells to transfer porphyrins from the lysosome to the cytosol. Our second specific aim will utilize a yeast model of erythropoietic protoporphyria (EPP) to identify the transport protein required to move protoporphyrin from the mitochondrial matrix to the cytosol. Collectively, these studies will define the transport mechanisms involved in the movement of porphyrin intermediates within and from cells. The identified transporters are potential associated risk factors that may explain the phenotypic diversity observed in the PCT and EPP phenotypes.
This project will identify proteins that transport intermediates of the heme synthesis pathway across cellular membranes. Identifying these proteins will aid in the treatment of the porphyric disorders.
|Medlock, Amy E; Shiferaw, Mesafint T; Marcero, Jason R et al. (2015) Identification of the Mitochondrial Heme Metabolism Complex. PLoS One 10:e0135896|
|Dailey, Harry A; Gerdes, Svetlana; Dailey, Tamara A et al. (2015) Noncanonical coproporphyrin-dependent bacterial heme biosynthesis pathway that does not use protoporphyrin. Proc Natl Acad Sci U S A 112:2210-5|
|Yien, Yvette Y; Robledo, Raymond F; Schultz, Iman J et al. (2014) TMEM14C is required for erythroid mitochondrial heme metabolism. J Clin Invest 124:4294-304|
|Phillips, John D; Kushner, James P; Bergonia, Hector A et al. (2011) Uroporphyria in the Cyp1a2-/- mouse. Blood Cells Mol Dis 47:249-54|
|To-Figueras, J; Phillips, J D; Gonzalez-LÃ³pez, J M et al. (2011) Hepatoerythropoietic porphyria due to a novel mutation in the uroporphyrinogen decarboxylase gene. Br J Dermatol 165:499-505|