cleavage of acyl CoA by ABC subfamily D transporters in peroxisomes: mechanism and functional roles
过氧化物酶体中 ABC 亚家族 D 转运蛋白对酰基 CoA 的裂解:机制和功能作用
基本信息
- 批准号:BB/L001012/1
- 负责人:
- 金额:$ 51.41万
- 依托单位:
- 依托单位国家:英国
- 项目类别:Research Grant
- 财政年份:2014
- 资助国家:英国
- 起止时间:2014 至 无数据
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
Cells of animals, plants and fungi are organised into compartments which have different functions, much like the rooms in a house. One such compartment is the peroxisome. The main role of peroxisomes is to release energy and molecular building blocks from stored fat and oil, a process called beta-oxidation. Beta-oxidation also plays other roles in making molecules that are important signals within and between cells and peroxisomes share several other jobs with different compartments in cells. For this to work efficiently, many different types of molecules have to move in and out of peroxisomes in an organised fashion. Thus, peroxisomes are sometimes called "organelles at the crossroads". This project aims to study a family of proteins which transport molecules into peroxisomes so that they can be processed by beta-oxidation. These proteins are called ATP Binding Cassette transporters from subfamily D, or ABCD transporters. We have been studying how these transporters work at a detailed level and also more globally, to determine how they help to keep the different chemical reactions of the cell in check. By investigating ABCD transporters, we have learned that beta-oxidation is important for seed germination and establishment, fertility, senescence, root growth and wound responses in plants and this tells us that the transporters accept quite a wide range of different molecules. Others have shown that ABCD transporters are important for fat breakdown in humans and when they do not work properly, can cause diseases. Recently, we have found that ABCD transporters are rather unusual because they accept a molecule such as a fatty acid which is joined to another molecule called Coenzyme A (CoA) but then chop off ("cleave") the CoA part as the fatty acid is transported into the peroxisome. CoA is an important chemical in cells because it helps different chemical reactions to happen, thus the levels in different compartments need to be carefully regulated. Once inside the peroxisome, the fatty acid cannot enter the beta-oxidation process until it is "activated"- by joining it to another CoA molecule. At first glance, this seems inefficient but we think that it is important for controlling which molecules can enter the peroxisome and be processed by beta-oxidation (this is known as "metabolic channelling"). Re-joining of the CoA molecule to fatty acids inside the peroxisome requires proteins called acyl activating enzymes (AAEs). We have shown that ABCD transporters in plants are physically and functionally linked to the AAEs which join fatty acids to CoA but we think that they could also interact with different AAEs which join other kinds of molecules to CoA. The availability of different AAEs and their interaction with the transporter provides a potential check-point to control which molecules are allowed to be processed by beta-oxidation.To understand this process better and to make the knowledge more widely useful, we now need to know more detail about how the transporters work, including how the CoA cleavage fits into the transport process and whether it works equally well for different molecules which can be imported. We also want to find out where the cleaved CoA ends up (outside the peroxisome or inside?). Taken together, this information will tell us how peroxisomes balance their resources between different competing functions and how metabolism is controlled.
动物、植物和真菌的细胞被组织成具有不同功能的隔间,就像房子里的房间一样。一个这样的隔室是过氧化物酶体。过氧化物酶体的主要作用是从储存的脂肪和油中释放能量和分子构建块,这一过程称为β-氧化。β-氧化在制造细胞内和细胞间的重要信号分子方面也发挥着其他作用,过氧化物酶体与细胞中的不同隔室共享其他几项工作。为了有效地发挥作用,许多不同类型的分子必须以有组织的方式进出过氧化物酶体。因此,过氧化物酶体有时被称为“十字路口的细胞器”。该项目旨在研究一个蛋白质家族,该家族将分子转运到过氧化物酶体中,以便它们可以通过β-氧化进行处理。这些蛋白质被称为来自亚家族D的ATP结合盒转运蛋白,或ABCD转运蛋白。我们一直在研究这些转运蛋白如何在详细的水平上以及更全面地工作,以确定它们如何帮助控制细胞的不同化学反应。通过研究ABCD转运蛋白,我们已经了解到β-氧化对于植物种子萌发和建立、生育力、衰老、根生长和创伤反应是重要的,这告诉我们转运蛋白接受相当广泛的不同分子。其他人已经表明,ABCD转运蛋白对人类的脂肪分解很重要,当它们不能正常工作时,可能会导致疾病。最近,我们发现ABCD转运蛋白是相当不寻常的,因为它们接受一种分子,如脂肪酸,该分子与另一种称为辅酶A(CoA)的分子连接,但随后在脂肪酸被转运到过氧化物酶体中时切断(“切割”)CoA部分。辅酶A是细胞中一种重要的化学物质,因为它有助于不同的化学反应发生,因此需要仔细调节不同隔室中的水平。一旦进入过氧化物酶体,脂肪酸就不能进入β-氧化过程,直到它被“激活”-通过将其加入另一个CoA分子。乍一看,这似乎效率低下,但我们认为这对于控制哪些分子可以进入过氧化物酶体并通过β-氧化进行处理(这被称为“代谢通道”)很重要。辅酶A分子重新连接到过氧化物酶体内的脂肪酸需要称为酰基活化酶(AAE)的蛋白质。我们已经证明,植物中的ABCD转运蛋白在物理上和功能上与将脂肪酸连接到CoA的AAE相关,但我们认为它们也可以与将其他类型的分子连接到CoA的不同AAE相互作用。不同AAE的可用性及其与转运蛋白的相互作用提供了一个潜在的检查点,以控制哪些分子被允许通过β-氧化处理。为了更好地理解这一过程,并使知识更广泛地使用,我们现在需要了解更多关于转运蛋白如何工作的细节,包括CoA裂解如何适应运输过程,以及它是否对可以输入的不同分子同样有效。我们还想知道切割的CoA最终在哪里(过氧化物酶体外部还是内部?)。总之,这些信息将告诉我们过氧化物酶体如何在不同的竞争功能之间平衡它们的资源,以及如何控制新陈代谢。
项目成果
期刊论文数量(7)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
The life of the peroxisome: from birth to death.
过氧化物酶体的生命:从出生到死亡。
- DOI:10.1016/j.pbi.2014.09.003
- 发表时间:2014
- 期刊:
- 影响因子:9.5
- 作者:Baker A
- 通讯作者:Baker A
The Saccharomyces cerevisiae ABC subfamily D transporter Pxa1/Pxa2p co-imports CoASH into the peroxisome.
酿酒酵母 ABC 亚科 D 转运蛋白 Pxa1/Pxa2p 将 CoASH 共同导入过氧化物酶体。
- DOI:10.1002/1873-3468.13974
- 发表时间:2021
- 期刊:
- 影响因子:3.5
- 作者:Van Roermund CWT
- 通讯作者:Van Roermund CWT
Plant ABC Transporters
植物 ABC 运输机
- DOI:10.1007/978-3-319-06511-3_6
- 发表时间:2014
- 期刊:
- 影响因子:0
- 作者:Theodoulou F
- 通讯作者:Theodoulou F
Peroxisomal ABC transporters: functions and mechanism.
- DOI:10.1042/bst20150127
- 发表时间:2015-10
- 期刊:
- 影响因子:3.9
- 作者:Baker A;Carrier DJ;Schaedler T;Waterham HR;van Roermund CW;Theodoulou FL
- 通讯作者:Theodoulou FL
How to move an amphipathic molecule across a lipid bilayer: different mechanisms for different ABC transporters?
- DOI:10.1042/bst20160040
- 发表时间:2016-06-15
- 期刊:
- 影响因子:3.9
- 作者:Theodoulou FL;Carrier DJ;Schaedler TA;Baldwin SA;Baker A
- 通讯作者:Baker A
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Alison Baker其他文献
Localization and targeting of isocitrate lyases in Saccharomyces cerevisiae.
酿酒酵母中异柠檬酸裂解酶的定位和靶向。
- DOI:
- 发表时间:
1996 - 期刊:
- 影响因子:4.1
- 作者:
Kathryn M Taylor;Claude P. Kaplan;Xiaoping Gao;Alison Baker - 通讯作者:
Alison Baker
Castor Bean Isocitrate Lyase Lacking the Putative Peroxisomal Targeting Signal 1 ARM Is Imported into Plant Peroxisomes Both in Vitro and in Vivo
缺乏假定的过氧化物酶体靶向信号的蓖麻子异柠檬酸裂解酶 1 ARM 在体外和体内均被导入植物过氧化物酶体中
- DOI:
- 发表时间:
1996 - 期刊:
- 影响因子:7.4
- 作者:
X. Gao;J. Marrison;Martin R. Pool;R. Leech;Alison Baker - 通讯作者:
Alison Baker
What to look for during constant observations: Expert consensus and a tool for observations recording.
在持续观察过程中要寻找什么:专家共识和观察记录工具。
- DOI:
10.1111/jpm.12555 - 发表时间:
2020 - 期刊:
- 影响因子:2.7
- 作者:
S. Chu;Katie Lambert;Alison Baker - 通讯作者:
Alison Baker
Exploring Underlying Dimensions of Social Connectedness in the Experiences of Suspended Young People from Ethnically Diverse Populations in the USA
探索美国不同种族人群中的悬浮年轻人经历中社会联系的潜在维度
- DOI:
- 发表时间:
2017 - 期刊:
- 影响因子:0
- 作者:
D. Henderson;Alison Baker;R. Goings;Berdine Gordon - 通讯作者:
Berdine Gordon
Resilience processes of brazilian young people: overcoming adversity through an arts program
巴西年轻人的韧性过程:通过艺术项目克服逆境
- DOI:
- 发表时间:
2018 - 期刊:
- 影响因子:0
- 作者:
A. Pessoa;Renata Maria Coimbra;C. S. Murgo;A. Breda;Alison Baker - 通讯作者:
Alison Baker
Alison Baker的其他文献
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{{ truncateString('Alison Baker', 18)}}的其他基金
India:Plant science for food security and nutrition
印度:植物科学促进粮食安全和营养
- 批准号:
BB/R021171/1 - 财政年份:2018
- 资助金额:
$ 51.41万 - 项目类别:
Research Grant
Regulation of polyphosphate metabolism in Chlamydomonas and potential for exploitation as P phosphorus sink in nutrient recovery systems
衣藻多磷酸盐代谢的调节及其在营养物回收系统中作为磷磷汇的开发潜力
- 批准号:
BB/N016033/1 - 财政年份:2016
- 资助金额:
$ 51.41万 - 项目类别:
Research Grant
A chemical genetic approach to the analysis of peroxisome biogenesis
分析过氧化物酶体生物发生的化学遗传学方法
- 批准号:
BB/E013740/1 - 财政年份:2007
- 资助金额:
$ 51.41万 - 项目类别:
Research Grant
Purification and functional characterisation of COMATOSE a peroxisomal ABC transporter from Arabidopsis thaliana
拟南芥过氧化物酶体 ABC 转运蛋白 COMATOSE 的纯化和功能表征
- 批准号:
BB/F007299/1 - 财政年份:2007
- 资助金额:
$ 51.41万 - 项目类别:
Research Grant
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高覆盖“拟”靶标Acyl-CoAs分析新策略及在非酒精性脂肪肝中的应用
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产油微藻LPCAT在正向和逆向反应中的底物特异性及其参与磷脂酰胆碱“酰基编辑”(acyl editing)的功能研究
- 批准号:31961133008
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心肌能源代谢和心力衰竭 -Acot1的作用及其调控机制研究
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海洋弧菌菌群感应信号分子N-acyl homoserine lactones对NK细胞的调控作用研究
- 批准号:31400107
- 批准年份:2014
- 资助金额:25.0 万元
- 项目类别:青年科学基金项目
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Acyl-CoA合成酵素ACSL3のオートファジーにおける役割の解明
阐明酰基辅酶 A 合成酶 ACSL3 在自噬中的作用
- 批准号:
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Ceramides as Novel Mediators of Very Long-Chain Acyl-CoA Dehydrogenase Deficiency-Induced Heart Failure.
神经酰胺作为极长链酰基辅酶A脱氢酶缺乏引起的心力衰竭的新型介体。
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10747561 - 财政年份:2023
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Discovery of Glutaryl-CoA Dehydrogenase inhibitors for melanoma and pancreatic cancer
发现治疗黑色素瘤和胰腺癌的戊二酰辅酶A脱氢酶抑制剂
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10347030 - 财政年份:2021
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Acyl-CoA synthetase-mediated regulation of lipid homeostasis
酰基辅酶A合成酶介导的脂质稳态调节
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10189414 - 财政年份:2021
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Discovery of Glutaryl-CoA Dehydrogenase inhibitors for melanoma and pancreatic cancer
发现治疗黑色素瘤和胰腺癌的戊二酰辅酶A脱氢酶抑制剂
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10536671 - 财政年份:2021
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Regulation of acyl-CoA-related enzymes by enzymatically inactive enzyme homolog
酶无活性酶同系物对酰基辅酶A相关酶的调节
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The effect of mitochondrial CoA degradation on glucose and fatty acid metabolism
线粒体CoA降解对葡萄糖和脂肪酸代谢的影响
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The effect of mitochondrial CoA degradation on glucose and fatty acid metabolism
线粒体CoA降解对葡萄糖和脂肪酸代谢的影响
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Structure and mechanism of mammalian stearoyl-CoA desaturases
哺乳动物硬脂酰辅酶A去饱和酶的结构和机制
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