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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：
Amer Alam
金额：
$ 17.5万
依托单位：
UNIVERSITY OF MINNESOTA
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：
https://reporter.nih.gov/project-details/10796495
关键词：
ACBD3 gene ATP-Binding Cassette Transporters Acceleration Adrenoleukodystrophy Bile Acid Biosynthesis Pathway Bile Acids Biochemical Biological Cells Chemicals Cryoelectron Microscopy Defect Development Diagnostic Disease Disease Pathway Electron Spin Resonance Spectroscopy Environment Family Fatty Acids Functional disorder Future Impairment In Vitro Lipids Liver diseases Metabolic Metabolic Diseases Molecular Molecular Conformation Mutation Neurologic Pathology Patient-Focused Outcomes Peroxisomal Disorders Phospholipids Physiological Property Regulation Resolution Role Structure Substrate Specificity Therapeutic Very Long Chain Fatty Acid Work branched chain fatty acid combat design drug development fatty acid metabolism fatty acid transport functional disability improved in silico in vitro Assay insight leukodystrophy nervous system disorder peroxisome rare genetic disorder stem tool

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