Molecular concepts that monitor methionine metabolism

监测蛋氨酸代谢的分子概念

基本信息

批准号：
9892665
负责人：
Peter Kaiser
金额：
$ 4.88万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-05-01 至 2022-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9892665
关键词：
Affect Amino Acids Animals Apoptosis Bacteria Biological Process CDC6 gene Caloric Restriction Calories Cell Cycle Cell Cycle Arrest Cell Cycle Checkpoint Cell Proliferation Cell division Cell physiology Cells Cellular Stress Chromatin DNA Dependence Development Diet Disease Drug Targeting Eating Epigenetic Process Event Goals Homocysteine Human Hypersensitivity Individual Investigation Link Literature Longevity Malignant Neoplasms Measures Metabolic Metabolic Pathway Metabolism Methionine Methionine Metabolism Pathway Methylation Molecular Monitor Nature Nutrient Organism Pathway interactions Physiology Positioning Attribute Pre-Replication Complex Protein Methylation Protein Phosphatase 2A Regulatory Subunit PR53 Proteins RNA RNA Caps RNA methylation Reaction Reporting Research Role S Phase S-Adenosylhomocysteine S-Adenosylmethionine Signal Pathway Signal Transduction Solid Neoplasm Structure System Therapeutic Tissues Translations Whole Organism Yeasts addiction age related cancer cell cancer therapy cell behavior insight interest leukemia new therapeutic target novel novel therapeutic intervention prevent response sensor tumor uptake

项目摘要

Project Summary Methionine occupies a special place among amino acids. This is best illustrated by the phenomenon called “methionine-dependence of cancer”. This cancer specific metabolic need describes the behavior of cells when grown in medium lacking methionine but supplemented with the immediate metabolic precursor homocysteine. Non-tumorigenic cells maintain their proliferation rate in homocysteine, but the vast majority of cancer cells, independent of their tissue origin, induce cell cycle arrest followed by apoptosis when cultured in homocysteine medium. Importantly, methionine- dependence is not only observed in cultured cancer cells. Solid tumors and leukemias also depend on high flux through the metabolic pathways connected to methionine. Furthermore, longevity is strikingly connected to dietary methionine uptake. Caloric restriction is well known to increase longevity in many organisms. This effect is mimicked by restricting methionine in an otherwise rich diet. Conversely, supplementing a low-calorie diet with methionine eliminates the benefits of caloric restriction for longevity. This proposal seeks understanding of the molecular effects that fluctuating methionine levels have on cellular and organismal physiology, as well as an explanation for the methionine dependence of cancer. Reports in the literature and our preliminary studies suggest that methionine uses unique signaling pathways that have not been explored at the molecular level. We find that the canonical amino acid and nutrient responsive TOR pathway is not involved in measuring or signaling methionine levels. Furthermore, the downstream metabolites S-adenosylmethionine (SAM) and S-adenosyl- homocysteine (SAH) — and not methionine itself — appear to be the effector metabolites for both the effects on cancer cell proliferation and longevity. SAM is the primary cellular methyl donor and the SAM/SAH ratio is generally considered the determinant of the cellular methylation potential. As such these metabolites are ideally positioned to signal methionine levels through specific methylation events. We have identified methylation events on groups of RNAs and specific proteins as candidates that link methionine levels to specific cellular responses. One goal of this proposal is to identify the critical RNAs and proteins that are controlled through methylation and show a hypersensitive response to fluctuations in methionine or SAM/SAH concentrations. The sensitive reaction to varying methylation allows these RNAs and proteins to trigger signals and ultimately cellular pathways that connect methionine metabolism to cell proliferation and other cellular functions. The second goal of the proposal is thus to identify these pathways and initiate investigation of how they connect metabolism with cell physiology at the molecular level. Understanding the molecular concepts that integrate methionine metabolism with other cellular functions promise new therapeutic strategies for treatment of cancer and other age-related disorders. Thus, this proposal aims to development molecular insight into a fundamental, so far molecularly unexplored, biological process with great potential for therapeutic exploitation.

项目概要蛋氨酸在氨基酸中占有特殊的地位，这一现象最好地说明了这一点。这种癌症特定的代谢需求被称为“癌症的蛋氨酸依赖性”。当细胞在缺乏蛋氨酸但补充了立即的培养基中生长时的行为代谢前体同型半胱氨酸。同型半胱氨酸，但绝大多数癌细胞，无论其组织来源如何，都会诱导细胞在同型半胱氨酸培养基中培养时，细胞周期停滞，随后发生细胞凋亡。重要的是，蛋氨酸-。依赖性不仅存在于培养的癌细胞中，实体瘤和白血病也存在依赖性。通过与蛋氨酸相关的代谢途径的高通量此外，寿命也很长。众所周知，热量限制会增加饮食中蛋氨酸的摄入量。在许多生物体中，通过限制蛋氨酸的含量来模拟这种效应。饮食。，线下用蛋氨酸补充低热量饮食消除了热量的好处长寿的限制。该提案旨在了解蛋氨酸水平波动对分子的影响细胞和生物生理学，以及对蛋氨酸依赖性的解释文献报告和我们的初步研究表明，蛋氨酸具有独特的用途。我们发现尚未在分子水平上探索的信号通路。氨基酸和营养响应 TOR 通路不参与蛋氨酸的测量或信号传导此外，下游代谢物 S-腺苷甲硫氨酸 (SAM) 和 S-腺苷- 同型半胱氨酸（SAH）——而不是蛋氨酸本身——似乎是这两种蛋白的效应代谢物。 SAM 是主要的细胞甲基供体和对癌细胞增殖和寿命的影响。 SAM/SAH 比率通常被认为是细胞甲基化潜力的决定因素。这些代谢物非常适合通过特定的甲基化来发出蛋氨酸水平信号我们已经确定了 RNA 组和特定蛋白质的甲基化事件作为候选事件。该提案的一个目标是确定蛋氨酸水平与特定细胞反应的关系。通过甲基化控制的关键 RNA 和蛋白质，表现出高度敏感对蛋氨酸或 SAM/SAH 浓度波动的响应对变化的敏感反应。甲基化允许这些 RNA 和蛋白质触发信号并最终触发细胞通路，将蛋氨酸代谢与细胞增殖和其他细胞功能联系起来。因此，建议确定这些路径并开始调查它们如何连接新陈代谢与分子水平上的细胞生理学。了解将蛋氨酸代谢与其他细胞整合的分子概念功能有望为治疗癌症和其他与年龄相关的疾病提供新的治疗策略。因此，该提案旨在将分子洞察力发展为迄今为止分子水平的基本原理未经探索的生物过程，具有巨大的治疗开发潜力。