Eukaryotic Heme Utilization

真核血红素利用

• 批准号: 7593673
• 负责人: Caroline Philpott
• 金额: $ 25.12万
• 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/7593673
• 关键词: Binding; Biochemical Genetics; Biological; Caenorhabditis elegans; Cell membrane; Cells; Collaborations; Condition; Copper; Enzymes; Eukaryota; Eukaryotic Cell; Friedreich Ataxia; Genes; Genetic; Heme; Heme Iron; Hemoglobin; Hereditary Disease; Hereditary hemochromatosis; Homeostasis; Human; Hypoxia; Intracellular Transport; Iron; Iron Compounds; Iron Overload; Mammals; Maryland; Metabolism; Microarray Analysis; Myoglobin; Numbers; Nutrient; Organic Iron Compounds; Organism; Oxygen; Porphyrins; Process; Regulation; Role; Saccharomyces cerevisiae; Saccharomycetales; System; Toxin; Universities; Yeasts; Zinc; cofactor; deprivation; expression vector; heme a; human disease; insight; iron metabolism; metal metabolism; microorganism; protoporphyrin IX; response; uptake

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 regulated genes from C. elegans will be cloned into yeast expression vectors and analyzed for heme uptake activity and their effects on intracellular pools of heme.

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。虽然酿酒酵母在铁缺乏时不吸收血红素，但我们已经确定，该物种确实具有在血红素缺乏和缺氧条件下激活的诱导血红素摄取系统。我们对在这些条件下生长的菌株进行了微阵列分析，发现许多假定的转运蛋白被转录激活。我们已经确定了转运蛋白，当过表达时，增加血红素摄取到酵母。我们还发现了一种转运蛋白，称为PUG1（卟啉摄取基因1），它可以刺激原卟啉IX（血红素的直接前体）的摄取，同时抑制血红素的利用。这种转运蛋白在缺氧和血红素缺乏的情况下被转录激活，并在酵母的质膜上表达。