权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Metabolic basis of the NADPH-independent disulfide reductase system in mouse liver

小鼠肝脏中不依赖 NADPH 的二硫键还原酶系统的代谢基础

基本信息

批准号：
10056616
负责人：
Gina Marie DeNicola
金额：
$ 44.73万
依托单位：
MONTANA STATE UNIVERSITY - BOZEMAN
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-14 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10056616
关键词：
Active Sites Adenosine Affect Anabolism Biliary Biology Bypass Carbon Catabolism Cells Coenzyme A Consumption Creatine Cysteine DNA DNA Methylation Dependence Disease Disulfides Enzymes Excretory function Feedback Folic Acid Future Generations Glutamates Glutathione Glutathione Disulfide Glutathione Reductase Glycine Health Hepatic Hepatocyte Homeostasis Inflammatory Institution Investigation Knockout Mice Knowledge Label Lead Lecithin Lipids Liver Malignant Neoplasms Mammalian Cell Metabolic Metabolic Pathway Metabolism Methionine Methylation Methyltransferase Microbe Modeling Mus NADP Natural regeneration Nerve Degeneration Normal Cell Nutrient Organoids Outcome Oxidants Oxidation-Reduction Oxidative Stress Oxidoreductase Pathogenicity Pathway interactions Patients Peripheral Physiological Positioning Attribute Predisposition Process Production Proteins RNA Reaction Regulation Resources Role Route S-Adenosylhomocysteine Serine Source Stable Isotope Labeling Stress Sulfur Sulfur Amino Acids Sulfur Metabolism Pathway System Testing Therapeutic Tissues Toxin Translations Vision Work amino acid metabolism base carbon skeleton clinical application combat histone methylation liver metabolism metabolomics methyl group mouse model novel therapeutic intervention oxidation oxidative damage pathogen prevent reaction rate regenerative response stable isotope therapeutic target thioredoxin reductase thioredoxin reductase 1 uptake

项目摘要

What is known: Disulfide reduction-fueled enzymes s!upport homeostasis and combat oxidative damage that contributes to neurodegeneration, inflammatory diseases, and cancer. NADPH provides the reducing power for most anabolic and cytoprotective reduction reactions, yet only two enzymes can use NADPH to reduce cytosolic disulfides: thioredoxin reductase-1 (TrxR1) and glutathione reductase (Gsr) 1. Both TrxR1 and Gsr have active sites that are dominantly inhibited by electrophilic toxins and oxidants 2, 3. In Co-PI Schmidt’s lab, mice with TrxR1/Gsr-null livers uncovered unexpected robustness in the disulfide reductase systems, including an NADPH-independent pathway that uses catabolism of methionine (Met) to sustain redox homeostasis 4. Importantly, this pathway is also thought to sustain normal cells under oxidative or electrophilic stress 5. Met and Cys are the 2 sulfur (S)-amino acids found in proteins, but S-containing molecules synthesized from Met or Cys, including S-adenosyl-Met (SAM), glutathione (GSH), CoA, and others, are also important in redox, detox, energetics, biosynthesis, regulation, and other processes. Co-PI DeNicola has been studying the roles of altered S-amino acid metabolism in sustaining some cancers6. These studies are revealing how some cancers use altered S-amino acid redox metabolism, which could uncover targetable cancer-specific susceptibilities. Unresolved questions: It remains unknown how other metabolic activities, including those that directly utilize Met or Cys, as well as more peripheral systems that either (i) supply resources to these pathways; (ii) depend upon these pathways; or (iii) might, in some conditions, compete with these pathways for substrates, are realigned to help cells survive stress. We hypothesize that conversion to Met-dependence involves realignment of diverse metabolic pathways. This work is significant because a better understanding of these processes will uncover processes that can be therapeutically targeted to either specifically increase the robustness of critical cells under oxidative or toxic stress, or specifically increase the vulnerability of pathogenic cells in cancer or inflammatory diseases. New preliminary investigations in this resubmission demonstrate our ability to perform stable isotope flux labeling studies in whole mice and in mouse-derived hepatic organoids. What is proposed: In this revised multi-institution collaborative project, we will define the metabolic pathway realignments that occur when hepatocytes switch from NADPH-dependent to -independent disulfide reduction. We propose 3 Specific Aims: Aim 1, Define how NADPH- versus Met-fueled disulfide reductase homeostasis influences S-metabolism prioritization. Aim 2, Define how re-wiring of serine metabolism supports Met-fueled disulfide reductase homeostasis. Aim 3, Test whether Met-dependent survival increases the activity and dependence on liver methyltransferases. Anticipated outcomes, value: This project will help us understand how global shifts in hepatic metabolism occurs in response to severe oxidative or electrophilic stress in liver, and how this helps sustain health.

已知的：二硫还原燃料酶！支持体内平衡和对抗氧化损伤