Comparative Heme Metabolism in Divergent Eukaryotes
不同真核生物中血红素代谢的比较
基本信息
- 批准号:10728411
- 负责人:
- 金额:$ 3.26万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-08-01 至 2024-05-31
- 项目状态:已结题
- 来源:
- 关键词:ApoptosisBindingBiochemicalBiogenesisBiologicalCellsChemistryComparative StudyDefectElectron TransportEnzymesErythrocytesEukaryotaEukaryotic CellGoalsHemeHumanLearningMediatingMetabolismMitochondriaMitochondrial MatrixMolecularOxidation-ReductionPeroxidasesPlasmodiumPlayProductionPropertyResearchRespirationRoleSignal TransductionSiteStructureTestingToxic effectWorkcofactorcomparativecytochrome cemerging pathogenheme-binding proteinhuman diseasehuman pathogeninsightmitochondrial dysfunctionparasite invasionpathogenpathogenic microbeprogramsthioetherthree dimensional structuretrafficking
项目摘要
PROJECT SUMMARY/ABSTRACT
Heme is an ancient biological cofactor that plays critical roles in mitochondrial redox chemistry, energy
production, and signaling in all eukaryotic cells from humans to microbial pathogens. Despite functional
similarities in their reliance on heme, divergent eukaryotes have evolved distinct molecular adaptations that tune
heme metabolism to particular cellular demands. Comparing and contrasting key features of mitochondrial heme
metabolism can thus reveal general principles in heme trafficking and utilization, as well as unveil unique
adaptations that highlight the evolutionary diversity among eukaryotes. Elucidating these general principles will
increase understanding of heme-related mitochondrial dysfunctions that underpin major human diseases.
Understanding of functional differences in heme metabolism can be exploited to develop new pathogen-specific
therapies that avoid human toxicity. In this proposal, we lay out a long-term goal of our research program
to deeply understand key biochemical properties and mechanisms of mitochondrial heme metabolism
in humans and a major human pathogen. In pursuing this goal over the next five years, we will focus our
studies on understanding the molecular mechanisms of biogenesis and function of cytochrome c, a critical and
tractable heme-binding protein with major unresolved mechanistic features that exemplifies key features of
mitochondrial heme metabolism and its conservation as well as diversity between eukaryotes. Cytochrome c has
a conserved essential function in the mitochondrial electron transport chain (ETC) but also plays an important,
separate role as a peroxidase that signals the onset of apoptosis. The molecular features of cytochrome c that
underpin its functional transition from ETC to peroxidase activity remain sparsely defined. Cytochrome c is
distinguished from other heme-binding proteins by its use of a conserved CXXCH sequence motif to covalently
bind heme via stable thioether bonds. This covalent attachment requires the mitochondrial intermembrane space
(IMS) enzyme, holo cytochrome c synthase (HCCS). Although HCCS function is fundamental to all eukaryotic
respiration, the structure of HCCS is unknown and thus molecular insight into its mechanism of attaching heme
to cytochrome c is lacking. Furthermore, it remains unknown how heme is trafficked to HCCS in the IMS from its
site of synthesis within the mitochondrial matrix. We propose comparative studies between human cells and
Plasmodium parasites that invade heme-rich human erythrocytes to tackle the following key challenges: 1) to
define the molecular features of cytochrome c that mediate its transition between ETC and peroxidase activities;
2) to elucidate the three-dimensional structure of HCCS and unravel its molecular mechanism of heme
attachment to cytochrome c; and 3) to determine the mechanism of heme acquisition by HCCS. This work will
advance fundamental understanding of mitochondrial heme metabolism in humans and a critical human
pathogen and provide a platform for longer-term integrative studies of heme metabolism that will test and extend
the lessons learned from our initial focus on cytochrome c.
项目概要/摘要
血红素是一种古老的生物辅助因子,在线粒体氧化还原化学、能量
从人类到微生物病原体的所有真核细胞中的生产和信号传导。尽管功能齐全
由于对血红素依赖的相似性,不同的真核生物进化出了不同的分子适应性,以调节
血红素代谢以满足特定的细胞需求。比较和对比线粒体血红素的主要特征
因此,新陈代谢可以揭示血红素运输和利用的一般原理,并揭示独特的机制。
突显真核生物进化多样性的适应。阐明这些一般原则将
增加对导致人类主要疾病的血红素相关线粒体功能障碍的了解。
对血红素代谢功能差异的理解可用于开发新的病原体特异性
避免人类毒性的疗法。在这份提案中,我们制定了研究计划的长期目标
深入了解线粒体血红素代谢的关键生化特性和机制
存在于人类中并且是主要的人类病原体。为实现这一目标,我们将在未来五年内集中精力
研究了解细胞色素 c 的生物发生和功能的分子机制,细胞色素 c 是一种关键且重要的细胞色素 c。
易于处理的血红素结合蛋白,具有主要未解决的机制特征,举例说明了
线粒体血红素代谢及其保守性以及真核生物之间的多样性。细胞色素c有
线粒体电子传递链 (ETC) 中保守的基本功能,但也发挥着重要作用,
作为过氧化物酶的单独作用,发出细胞凋亡开始的信号。细胞色素c的分子特征
其从 ETC 到过氧化物酶活性的功能转变的基础仍然很少被定义。细胞色素c是
与其他血红素结合蛋白的区别在于它使用保守的 CXXCH 序列基序来共价结合
通过稳定的硫醚键结合血红素。这种共价连接需要线粒体膜间隙
(IMS) 酶,全细胞色素 C 合酶 (HCCS)。尽管 HCCS 功能是所有真核生物的基础
呼吸作用,HCCS 的结构未知,因此从分子角度了解其附着血红素的机制
缺乏细胞色素c。此外,目前尚不清楚血红素是如何从其转运到 IMS 中的 HCCS 的。
线粒体基质内的合成位点。我们提出了人体细胞和
疟原虫寄生虫侵入富含血红素的人类红细胞,以应对以下关键挑战:1)
定义介导 ETC 和过氧化物酶活性之间转换的细胞色素 c 的分子特征;
2)阐明HCCS的三维结构,揭示其血红素的分子机制
附着于细胞色素 c; 3) 确定 HCCS 获取血红素的机制。这项工作将
促进对人类和关键人类线粒体血红素代谢的基本了解
病原体并为血红素代谢的长期综合研究提供一个平台,该平台将测试和扩展
从我们最初关注细胞色素 c 中吸取的经验教训。
项目成果
期刊论文数量(3)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Multiple-Streams Focusing-Based Cell Separation in High Viscoelasticity Flow.
- DOI:10.1021/acsomega.2c06021
- 发表时间:2022-11-15
- 期刊:
- 影响因子:4.1
- 作者:Feng, Haidong;Patel, Dhruv;Magda, Jules J.;Geher, Sage;Sigala, Paul A.;Gale, Bruce K.
- 通讯作者:Gale, Bruce K.
In the name of perseverance.
- DOI:10.7554/elife.92403
- 发表时间:2023-09-05
- 期刊:
- 影响因子:7.7
- 作者:Espino-Sanchez T
- 通讯作者:Espino-Sanchez T
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Paul A Sigala其他文献
Paul A Sigala的其他文献
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{{ truncateString('Paul A Sigala', 18)}}的其他基金
Comparative Heme Metabolism in Divergent Eukaryotes
不同真核生物中血红素代谢的比较
- 批准号:
9982387 - 财政年份:2019
- 资助金额:
$ 3.26万 - 项目类别:
Comparative Heme Metabolism in Divergent Eukaryotes
不同真核生物中血红素代谢的比较
- 批准号:
10618985 - 财政年份:2019
- 资助金额:
$ 3.26万 - 项目类别:
Comparative Heme Metabolism in Divergent Eukaryotes
不同真核生物中血红素代谢的比较
- 批准号:
10159278 - 财政年份:2019
- 资助金额:
$ 3.26万 - 项目类别:
Comparative Heme Metabolism in Divergent Eukaryotes
不同真核生物中血红素代谢的比较
- 批准号:
10615301 - 财政年份:2019
- 资助金额:
$ 3.26万 - 项目类别:
Comparative Heme Metabolism in Divergent Eukaryotes
不同真核生物中血红素代谢的比较
- 批准号:
10404110 - 财政年份:2019
- 资助金额:
$ 3.26万 - 项目类别:
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