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.
项目总结
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
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专利数量(0)
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Amer Alam其他文献
Amer Alam的其他文献
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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:
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10212863 - 财政年份:2021
- 资助金额:
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