The Biological Role of Heme in Human Nutrition

产品说明：血红素（铁-原卟啉IX）是蛋白质的辅基，其在许多生物过程中发挥关键作用，包括氧化代谢、双原子气体的合成和感测、细胞分化、异生物质解毒、转录水平的基因调控、蛋白质翻译和靶向以及蛋白质稳定性。 人类利用血红素作为来自红肉的铁的来源，因为血红素在肠道中比无机铁更容易吸收。 在真核生物中，血红素在线粒体内合成。 游离血红素在水环境中不溶，并且由于过氧化物酶活性而具有细胞毒性。 因此，可以提出一个初步的论点，即在细胞内存在特定的途径，用于将血红素从合成位点运输到各种细胞内目的地，用于将血红素掺入脱辅基血红素蛋白。 血红素是通过一个多步骤的生物合成途径与明确的中间体，被认为是高度保守的整个进化。 这些研究的长期目标是确定哺乳动物系统中营养血红素稳态的分子和细胞决定因素。 本研究将利用C.线虫作为遗传模式生物，以阐明血红素摄取，螯合，运输和纳入血红素蛋白的途径。 探讨了C.将通过使用荧光血红素类似物的显微镜、脉冲追踪分析和使用[59 Fe]血红素的代谢标记的血红素摄取和掺入测定来评估秀丽线虫。 血红素在C.将通过筛选和分类在正常生长和发育中具有血红素依赖性缺陷的突变体来鉴定秀丽线虫。 突变体将进行生化表征，突变将通过遗传重组和SNP作图进行定位和定位。 这些研究的结果将为真核生物中血红素的稳态提供新的机制见解，并可能有助于开发基于血红素的营养干预措施来治疗人类铁缺乏症，并允许设计新的药物靶点来调节外源性物质代谢。

DESCRIPTION: Heme (iron-protoporphyrin IX) is the prosthetic group of proteins which play a key role in many biological processes including oxidative metabolism, the synthesis and sensing of diatomic gases, cellular differentiation, xenobiotic detoxification, gene regulation at the level of transcription, protein translation and targeting, and protein stability. Humans utilize heme as a source of iron from red meat because heme is more readily absorbed than inorganic iron in the intestine. In eukaryotes, heme is synthesized within the mitochondria. Free heme is insoluble in aqueous milieu and is cytotoxic due to peroxidase activity. Thus, a prima facie argument can be made that within cells specific pathways exist for the trafficking of heme from site of synthesis to various intracellular destinations for the incorporation of heme into apo-hemoproteins. Heme is synthesized via a multistep biosynthetic pathway with well-defined intermediates that were thought to be highly conserved through out evolution. The long-term objective of these studies is to define the molecular and cellular determinants of nutritional heme homeostasis in mammalian systems. The proposed studies will utilize C. elegans as a genetic model organism to elucidate pathways for heme uptake, sequestration, trafficking, and incorporation into hemoproteins. The biochemical mechanisms for heme acquisition in C. elegans will be evaluated by microscopy using fluorescent heme analogs, pulse-chase analysis, and heme uptake and incorporation assays using metabolic labeling with [59Fe]heme. The molecular and cellular pathways for heme trafficking in C. elegans will be identified by screening and classifying mutants that have heme-dependent defects in normal growth and development. The mutants will be charaterized biochemically, and the mutations will be mapped and localized by genetic recombination and SNP mapping. The results from these studies will provide new mechanistic insights into heme homeostasis in eukaryotes and may aid in the development of heme-based nutritional interventions for human iron deficiency, and permit design of novel drug targets to modulate xenobiotic metabolism.