Molecular Basis of Propionate Toxicity

丙酸盐毒性的分子基础

基本信息

批准号：
7677204
负责人：
JORGE C ESCALANTE
金额：
$ 21.5万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-02-12 至 2011-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7677204
关键词：
2-methylcitrate Acetates Acyl Coenzyme A Acylation Address Affect Anabolism Animal Model Animals Archaea Bacteria Biochemical Biochemical Pathway Biological Carbon Catabolism Cell Wall Cell physiology Cells Chemistry Chromosomes Citrate (si)-Synthase Citric Acid Cycle Coenzymes Communicable Diseases Complex Data Ensure Enzymes Ethanolamines Eukaryota Food Preservatives Gastrointestinal tract structure Gene Expression Genes Genetic Gluconeogenesis Glucose Growth Growth Inhibitors Health Histones Human Isomerism Knowledge Laboratories Learning Ligase Light Metabolic Metabolism Microbe Molecular Molecular Genetics Mutation Nucleic Acids Phenotype Physiological Play Prevention Prokaryotic Cells Propionates Propylene Glycols Proteins Publishing Research Personnel Ribose Role Salmonella enterica Sirtuins Soil Solid Source Substrate Specificity System Toxic effect Volatile Fatty Acids Work base cell growth cobamamide deacylation enzyme activity fatty acid metabolism gene function gut microflora inhibitor/antagonist insight interdisciplinary approach interest nutrition pathogen prevent propionyl-coenzyme A public health relevance stereochemistry

项目摘要

DESCRIPTION (provided by applicant): Propionate is a three-carbon short-chain fatty acid that is very abundant in soil and the gastrointestinal tracts of animals, including humans. Propionate is widely used as a food preservative because it inhibits the growth of pathogenic and non-pathogenic prokaryotes and lower eukaryotes, but it does not affect human cells. The inhibitory effects of propionate have been attributed to the build up of the activated form of propionate, i.e., propionyl-coenzyme A (Pr-CoA). We have challenged this idea on the basis of published and unpublished data obtained from our group. In this application we propose to investigate the molecular basis of propionate toxicity. Our interpretation of the data suggests that growth arrest caused by propionate is the result of the synthesis of a non-physiological isomer of 2-methylcitrate by the citrate synthase (GltA) enzyme of the Krebs cycle; we refer to this inhibitor as 2-MCGltA. Our data suggest that 2-MCGltA inhibits an enzyme of gluconeogenesis. The lack of glucose has multiple negative effects. For example, cell wall and ribose syntheses are blocked, rendering the cell sensitive to osmotic changes and unable to make nucleic acids and coenzymes. One specific aim focuses on the identification and characterization of the target of 2-MCGltA. We seek to learn how 2-MCGltA inhibits the activity of the target, and whether the inhibitory effect of 2-MCGltA is stereospecific. A second specific aim focuses on the identification and analysis of ancillary functions needed to prevent propionate toxicity, and proteins involved in transporting propionate into the cell. PUBLIC HEALTH RELEVANCE: The project proposed in this application will provide insights into how propionate (a food preservative) exerts its inhibitory effects on cell growth at the molecular level. This work is relevant to human health and nutrition since propionate affects pathogenic and non-pathogenic microbes alike.

描述（由申请人提供）：丙酸酯是一种三碳短链脂肪酸，在包括人类在内的动物的土壤和胃肠道中非常丰富。丙酸酯被广泛用作食品防腐剂，因为它抑制了致病性和非致病性原核生物的生长和较低的真核生物的生长，但不会影响人类细胞。丙酸酯的抑制作用归因于丙酸激活形式的积累，即丙酰辅酶A（PR-COA）。我们根据从我们小组获得的已发布和未发表的数据挑战了这一想法。在此应用中，我们建议研究丙酸毒性的分子基础。我们对数据的解释表明，由丙酸丙酸酯引起的生长停滞是由克雷布斯循环的柠檬酸合酶（GLTA）酶合成2-甲基c的非生理异构体的结果。我们将此抑制剂称为2-MCGLTA。我们的数据表明，2-MCGLTA抑制糖异生的酶。缺乏葡萄糖会产生多种负面影响。例如，细胞壁和核糖合成被阻断，使细胞对渗透变化敏感，无法制造核酸和辅酶。一个具体的目的是介绍2-MCGLTA目标的识别和表征。我们试图学习2-MCGLTA如何抑制目标的活性，以及2-MCGLTA的抑制作用是否是立体特异性的。第二个特定目的侧重于鉴定和分析防止丙酸毒性所需的辅助功能，以及参与丙酸酯转运到细胞的蛋白质。公共卫生相关性：本申请中提出的项目将提供有关丙酸（食品防腐剂）如何在分子水平上对细胞生长产生抑制作用的见解。这项工作与人类健康和营养有关，因为丙酸酯会影响致病性和非致病微生物。