Molecular basis of fatty acid transport by peroxisomal ABC transporters
过氧化物酶体 ABC 转运蛋白转运脂肪酸的分子基础
基本信息
- 批准号:10796495
- 负责人:
- 金额:$ 17.5万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-09-01 至 2026-07-31
- 项目状态:未结题
- 来源:
- 关键词:ACBD3 geneATP-Binding Cassette TransportersAccelerationAdrenoleukodystrophyBile Acid Biosynthesis PathwayBile AcidsBiochemicalBiologicalCellsChemicalsCryoelectron MicroscopyDefectDevelopmentDiagnosticDiseaseDisease PathwayElectron Spin Resonance SpectroscopyEnvironmentFamilyFatty AcidsFunctional disorderFutureImpairmentIn VitroLipidsLiver diseasesMetabolicMetabolic DiseasesMolecularMolecular ConformationMutationNeurologicPathologyPatient-Focused OutcomesPeroxisomal DisordersPhospholipidsPhysiologicalPropertyRegulationResolutionRoleStructureSubstrate SpecificityTherapeuticVery Long Chain Fatty AcidWorkbranched chain fatty acidcombatdesigndrug developmentfatty acid metabolismfatty acid transportfunctional disabilityimprovedin silicoin vitro Assayinsightleukodystrophynervous system disorderperoxisomerare genetic disorderstemtool
项目摘要
Project Summary
Peroxisomal ABC transporters like ABCD1, ABCD2, and ABCD3 shuttle very long chain fatty acids (VLCFAs),
branched chain fatty acids (BCFAs), and bile acid precursors into peroxisomes. Their functional impairment leads
to severe neurological and metabolic pathologies stemming from disrupted phospholipid and fatty acid
metabolism, including X-linked Adrenoleukodystrophy (X-ALD), both the most common leukodystrophy and most
common peroxisomal disorder that is caused by mutations in ABCD1 and for which no cure exists, and bile acid
synthesis defects and liver disease stemming from impaired ABCD3 function. While additional roles for ABCD
transporters in a wider array of disease pathways continue to be uncovered, the underlying mechanisms
governing their substrate recognition, transport, and transport regulation remain poorly understood. The long-
term objectives of this project are to gain insight into peroxisomal ABCD transporter function and regulation in
molecular detail. We will use a combination of biochemical and cell biological tools, high resolution structural
analysis by cryo-electron microscopy, and continuous wave electron paramagnetic resonance (CW-EPR)
spectroscopy to reveal the functionally relevant structural features and conformational states used by ABCD
transporters in fatty acid translocation, how they may be altered by ABCD1 mutation in X-ALD, and how ABCD1
is mechanistically distinct from ABCD2 and ABCD3 despite their functional overlap. Specific Aim 1 deals with
the development and utilization of in vitro assays for determining substrate specificity profiles and transport
properties of ABCD1, ABCD2, and ABCD3. Specific Aim 2 deals with obtaining high resolution structural
information of ABCD1, ABCD2, and ABCD3 in functionally relevant states in a physiological lipid environment
through cryo-EM analysis. Specific Aim 3 deals obtaining information on the structural dynamics of ABCD1
through CW-EPR studies. Our results will provide fundamental insights into peroxisomal ABC transporter
functioning that can be exploited for ABCD1 targeted diagnostic and therapeutic tools to improve X-ALD patient
outcomes, provide a framework for the design and development of chemical probes to study ABCD family
function, and generate reliable in vitro and in silico tools to accelerate drug development/discovery efforts
targeting them.
项目概要
过氧化物酶体 ABC 转运蛋白如 ABCD1、ABCD2 和 ABCD3 穿梭极长链脂肪酸 (VLCFA),
支链脂肪酸(BCFA)和胆汁酸前体转化为过氧化物酶体。他们的功能障碍导致
因磷脂和脂肪酸破坏而引起的严重神经和代谢病变
代谢障碍,包括 X 连锁肾上腺脑白质营养不良 (X-ALD),这既是最常见的脑白质营养不良,也是最常见的脑白质营养不良
由 ABCD1 突变引起且无法治愈的常见过氧化物酶体疾病,以及胆汁酸
ABCD3 功能受损导致合成缺陷和肝病。而 ABCD 的附加角色
更广泛的疾病途径中的转运蛋白不断被发现,其潜在机制
其底物识别、运输和运输调节的控制仍然知之甚少。长-
该项目的长期目标是深入了解过氧化物酶体 ABCD 转运蛋白的功能和调节
分子细节。我们将结合使用生化和细胞生物学工具、高分辨率结构
通过冷冻电子显微镜和连续波电子顺磁共振 (CW-EPR) 进行分析
光谱揭示 ABCD 使用的功能相关结构特征和构象状态
脂肪酸易位中的转运蛋白,X-ALD 中 ABCD1 突变如何改变它们,以及 ABCD1 如何改变
尽管功能重叠,但在机制上与 ABCD2 和 ABCD3 不同。具体目标 1 涉及
开发和利用体外测定来确定底物特异性概况和运输
ABCD1、ABCD2 和 ABCD3 的性质。具体目标 2 涉及获得高分辨率结构
ABCD1、ABCD2 和 ABCD3 在生理脂质环境中处于功能相关状态的信息
通过冷冻电镜分析。具体目标 3 涉及获取 ABCD1 的结构动力学信息
通过 CW-EPR 研究。我们的结果将为过氧化物酶体 ABC 转运蛋白提供基本见解
可用于 ABCD1 靶向诊断和治疗工具以改善 X-ALD 患者的功能
结果,为研究 ABCD 家族的化学探针的设计和开发提供框架
功能,并生成可靠的体外和计算机工具来加速药物开发/发现工作
针对他们。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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{{ truncateString('Amer Alam', 18)}}的其他基金
Molecular basis of fatty acid transport by peroxisomal ABC transporters
过氧化物酶体 ABC 转运蛋白转运脂肪酸的分子基础
- 批准号:
10700981 - 财政年份:2022
- 资助金额:
$ 17.5万 - 项目类别:
ABCA7 dysfunction in Alzheimer's disease pathogenesis
ABCA7 功能障碍在阿尔茨海默病发病机制中的作用
- 批准号:
10212863 - 财政年份:2021
- 资助金额:
$ 17.5万 - 项目类别:
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