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Functional characterization of a mitochondrial orphan enzyme

线粒体孤儿酶的功能表征

基本信息

批准号：
9120683
负责人：
Hongying Shen
金额：
$ 5.46万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-08-01 至 2017-07-06
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9120683
关键词：
ATP Synthesis Pathway Acetyl Coenzyme A Amino Acids Anemia Biochemical Biochemistry Biological Assay CRISPR/Cas technology Carbon Cell Line Cells Cellular biology Cholesterol Citrates Citric Acid Cycle Coenzyme A Complement Complex Cultured Cells Detection Disease Enzymes Epitopes Exhibits Genes Genetic Genome engineering Genomics Goals Health Heart Heart Diseases Housing Human Human Activities Human Genetics Human Genome In Vitro Knock-out Label Laboratories Light Link Lipids Lyase Malates Mammals Mass Spectrum Analysis Mediating Metabolic Metabolic Pathway Metabolism Methionine Methods Methylmalonic Acid Methylmalonyl-CoA Mutase Mitochondria Mitochondrial Matrix Molecular Mutase Neurologic Dysfunctions Organelles Orphan Pathway interactions Physiological Physiology Play Population Process Propionic Acids Proteins Proteome Reaction Recombinants Recycling Regulation Research Role Techniques Testing Transcript Variant Vitamin B 12 Western Blotting Work base cell growth cobamamide cofactor genome wide association study glyoxylate human disease in vivo inhibitor/antagonist insight knock-down loss of function loss of function mutation lymphoblast metabolomics mitochondrial metabolism novel oxidation public health relevance skills small molecule thioester trait transcriptome sequencing

项目摘要

DESCRIPTION (provided by applicant): The long-term goal of the proposal is to decipher the function of mitochondrial orphan enzymes and their regulations on unexplored metabolic pathways with potential implications for human diseases. Mitochondria are intracellular organelles that house not only the machinery for ATP synthesis and fuel oxidation, but also metabolic enzymes for synthesis of building blocks for cell growth. For instance, a critical mitochondrial enzyme methylmalonyl-CoA mutase (MUT) recycles branched carbon chains from amino acids and lipids into tricarboxylic acid cycle. This process is critically dependent on an essential coenzyme vitamin B12 (B12). This project focuses on the role played by CLYBL, a ubiquitously expressed mitochondrial enzyme of unknown function, in regulating mitochondrial B12 function. A loss-of-function variant of CLYBL has been linked to subclinical B12 deficiency by two recent human genome-wide association studies. This proposal builds on the computational genomics analysis performed in our laboratory, which suggested CLYBL lies at the heart of a novel mitochondrial metabolic pathway connecting to B12-dependent MUT function. The proposed research seeks to understand: (1) enzymatic activities of CLYBL; (2) the CLYBL-dependent regulation of mitochondrial B12 function; and (3) molecular mechanism underlying this regulation. These studies will take advantage of the laboratory's expertise in advanced mass spectrometry-based metabolomics, computational genomics and mitochondrial physiology, combined with my skills in biochemistry and cell biology, to decipher the physiological function of CLYBL. This study of CLYBL represents a great example of "reverse human genetics". This work promises to shed new insights on mitochondrial biochemistry with potential implications for human diseases.