Novel lipoate-binding proteins and their role in sulfur oxidation

新型硫辛酸结合蛋白及其在硫氧化中的作用

基本信息

项目摘要

Lipoic acid (1,2-dithiolane-3-pentanoic acid) is a highly conserved organosulfur cofactor found in almost all prokaryotic and eukaroytic organisms. The cofactor is essential for the function of several key enzymes involved in oxidative and one-carbon metabolism. So far, only five lipoate-dependent multi¬enzyme complexes have been characterized: three α-ketoacid dehydrogenases (e.g. pyruvate dehydrogenase), acetoin dehydrogenase and the glycine cleavage complex.Although the existence of lipoic acid has been known for more than sixty years, our recent work revealed an unexpected metabolic function for this cofactor that is markedly different from its canonical roles in central metabolism. We proved that a novel lipoate-binding proteins (LbpA) act as indispensable components of a new pathway of dissimilatory sulfur oxidation. A heterodisulfide reductase (Hdr)-like complex is a central player in this pathway. It occurs in a huge organism group that includes biotechnologically and environmentally relevant bacteria like the volatile organic sulfur compound degrading Alphaproteobacerium Hyphomicrobium denitrificans and many chemolithoautotrophic bacteria and archaea. In all cases known so far, lipoate acts as a swinging arm that channels bound substrate between the active sites of different subunits. During catalysis, the intramolecular disulfide bond of lipoate cycles between oxidized lipoamide and reduced dihydrolipoamide and the electrons released upon reoxidation of dihydroliponamide can be directly transferred onto NAD+ via dihydroliponamide dehydrogenase. If lipoate-binding proteins perform similar functions in Hdr-dependent sulfur oxidation, then at least some of the electrons released here could be used directly for the formation of NADH. Such a reaction would considerably reduce the need for energy-demanding reverse electron flow in sulfur-oxidizing lithoautotrophs. Direct biochemical or genetic evidence for these exciting suggestions is currently not available. In this project, we aim at at filling this gap and intend to clarify the exact role of the novel lipoate binding proteins during sulfur oxidation. The following major questions will be addressed: [1] Do LbpA proteins function as sulfur-binding entities presenting substrate to different catalytic sites of the new heterodisulfide reductase-like sulfur-oxidizing complex? [2] Does lipoate switch between its oxidized and reduced forms during the catalytic cycle of the Hdr-like complex such that at least part of the electrons released during Hdr-driven sulfur oxidation can be directly used for generation of NADH? [3] Which other sulfur transferases are involved in the process?
硫辛酸(1,2-二硫戊环-3-戊酸)是一种高度保守的有机硫辅因子,存在于几乎所有的原核生物和真核生物中。辅因子是参与氧化和一碳代谢的几种关键酶的功能所必需的。到目前为止,只有五种硫辛酸依赖性多酶复合物被表征:三种α-酮酸脱氢酶(例如丙酮酸脱氢酶),乙偶姻脱氢酶和甘氨酸裂解复合物。虽然人们已经知道硫辛酸的存在超过60年,但我们最近的工作揭示了这种辅因子的意想不到的代谢功能,与其在中枢代谢中的典型作用明显不同。我们证明了一种新的脂酸结合蛋白(LbpA)作为一个新的异化硫氧化途径的不可或缺的组成部分。异二硫还原酶(Hdr)样复合物是这一途径的核心参与者。它发生在一个巨大的生物群中,包括生物技术和环境相关的细菌,如挥发性有机硫化合物降解Alphaproteobacerium Hyphomicrobium acerificans和许多化能自养细菌和古细菌。在所有已知的情况下,到目前为止,lipoate作为一个摆动的手臂,渠道结合底物之间的活性位点的不同亚基。在催化过程中,氧化硫辛酰胺和还原二氢硫辛酰胺之间的分子内二硫键和二氢硫辛酰胺再氧化时释放的电子可以通过二氢硫辛酰胺脱氢酶直接转移到NAD+上。如果脂酸结合蛋白在Hdr依赖的硫氧化中发挥类似的功能,那么这里释放的至少一些电子可以直接用于形成NADH。这样的反应将大大减少硫氧化岩石自养生物中需要能量的反向电子流的需要。这些令人兴奋的建议目前还没有直接的生物化学或遗传学证据。在这个项目中,我们的目标是填补这一空白,并打算澄清硫氧化过程中的新的硫辛酸结合蛋白的确切作用。以下主要问题将得到解决:[1] LbpA蛋白是否作为硫结合实体将底物呈递到新的异二硫键还原酶样硫氧化复合物的不同催化位点?[2]在Hdr-样复合物的催化循环期间,硫辛酸盐是否在其氧化和还原形式之间切换,使得在Hdr-驱动的硫氧化期间释放的至少部分电子可以直接用于生成NADH?[3]还有哪些硫转移酶参与了这一过程?

项目成果

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Privatdozentin Dr. Christiane Dahl其他文献

Privatdozentin Dr. Christiane Dahl的其他文献

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{{ truncateString('Privatdozentin Dr. Christiane Dahl', 18)}}的其他基金

Thiosulfate dehydrogenase: an unusual acidophilic c-type cytochrome
硫代硫酸脱氢酶:一种不寻常的嗜酸c型细胞色素
  • 批准号:
    198187081
  • 财政年份:
    2011
  • 资助金额:
    --
  • 项目类别:
    Research Grants
Sulfurtransferases as essential players during dissimilatory sulfur oxidation
硫转移酶是异化硫氧化过程中的重要参与者
  • 批准号:
    184061176
  • 财政年份:
    2010
  • 资助金额:
    --
  • 项目类别:
    Research Grants
Microbial utilization, mobilization and uptake of elemental sulfur
微生物对元素硫的利用、动员和吸收
  • 批准号:
    53653806
  • 财政年份:
    2007
  • 资助金额:
    --
  • 项目类别:
    Research Grants
Thiosulfate oxidation in sulfur-storing bacteria
储硫细菌中的硫代硫酸盐氧化
  • 批准号:
    5418530
  • 财政年份:
    2004
  • 资助金额:
    --
  • 项目类别:
    Research Grants
The oxidation of stored sulfur in phototrophic sulfur bacteria
光养硫细菌中储存的硫的氧化
  • 批准号:
    5301832
  • 财政年份:
    2001
  • 资助金额:
    --
  • 项目类别:
    Research Grants
A novel pathway of sulfur oxidation: The heterodisulfide reductase-like system
硫氧化的新途径:类异二硫键还原酶系统
  • 批准号:
    324957771
  • 财政年份:
  • 资助金额:
    --
  • 项目类别:
    Research Grants
Bacterial lipoate synthesis revisited: novel enzymes, unusual substrates and new evolutionary perspectives
重新审视细菌硫辛酸合成:新型酶、不寻常的底物和新的进化视角
  • 批准号:
    525834735
  • 财政年份:
  • 资助金额:
    --
  • 项目类别:
    Research Grants

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新型磷酸盐结合剂:对高磷血症、血管钙化的影响
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NSAID 阿尔茨海默病预防机制
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靶向阿尔茨海默病淀粉样蛋白的硫辛酸衍生物
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    --
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Lipoate Derivatives Targeting Alzheimer's Amyloid
靶向阿尔茨海默病淀粉样蛋白的硫辛酸衍生物
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硫辛酸途径在疟原虫存活中的作用
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Roles of Lipoate Pathways in Plasmodium Survival
硫辛酸途径在疟原虫存活中的作用
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