Eukaryotic Heme Utilization

真核血红素利用

• 批准号: 8741499
• 负责人: Caroline Philpott
• 金额: $ 20.22万
• 依托单位: NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8741499
• 关键词: Binding; Biochemical; Biological; Caenorhabditis elegans; Cells; Collaborations; Copper; Cytosol; Environment; Enzymes; Eukaryota; Exhibits; Friedreich Ataxia; Genes; Genetic; Genetic Screening; Heme; Heme Iron; Hemoglobin; Hereditary Disease; Hereditary hemochromatosis; Homeostasis; Human; Intracellular Transport; Iron; Iron Compounds; Iron Overload; Leishmania; Mammals; Maryland; Metabolism; Mitochondria; Myoglobin; Nutrient; Organic Iron Compounds; Organism; Oxygen; Process; Proteins; Regulation; Role; Saccharomyces cerevisiae; Saccharomycetales; Site; System; Toxin; Universities; Virulence; Yeasts; Zinc; aqueous; cofactor; deprivation; design; heme a; human disease; insight; iron metabolism; loss of function; metal metabolism; microorganism; mutant; pathogen; response; trafficking; uptake; yeast protein

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.

我们对真核生物中血红素的转运知之甚少，在酵母中也没有发现血红素特异性转运摄取系统。血红素在线粒体中合成，但辅因子在整个细胞的隔室中使用。血红素是高度疏水性的，不太可能被释放到细胞质的水环境中，这表明血红素在细胞内运输存在机制。我们已经设计了一个基因筛选酵母蛋白参与细胞内血红素运输的鉴定，并正在评估候选人。在这个筛选中发现的基因表明血红素通过囊泡运输系统从线粒体移动到其他位置。