Molecular concepts that monitor methionine metabolism

监测蛋氨酸代谢的分子概念

• 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
• 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

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.

项目摘要 蛋氨酸在氨基酸中占有特殊的地位。最能说明这一点的是 称为“癌症的蛋氨酸依赖”。这种癌症特异性代谢需要描述了 当在缺乏甲硫氨酸但补充有直接甲硫氨酸的培养基中生长时细胞的行为 代谢前体同型半胱氨酸。非致瘤性细胞维持其增殖率， 但是绝大多数癌细胞，不依赖于它们的组织来源，诱导细胞凋亡， 在同型半胱氨酸培养基中培养时，细胞周期停滞，随后细胞凋亡。重要的是，蛋氨酸- 依赖性不仅在培养的癌细胞中观察到。实体瘤和白血病也依赖于 通过与甲硫氨酸相连的代谢途径的高通量。此外，长寿是 与饮食中甲硫氨酸的摄取有着惊人的联系。众所周知，热量限制会增加 在许多生物体中的寿命。这种效果是模仿限制蛋氨酸，否则丰富的 饮食.相反，补充蛋氨酸的低热量饮食消除了热量的好处， 限制寿命。 该提案旨在了解蛋氨酸水平波动对 细胞和有机体生理学，以及对蛋氨酸依赖性的解释， 癌文献报告和我们的初步研究表明，蛋氨酸使用独特的 这些信号通路尚未在分子水平上探索。我们发现， 氨基酸和营养素响应性TOR途径不参与测量或信号传导甲硫氨酸 程度.此外，下游代谢物S-腺苷甲硫氨酸（SAM）和S-腺苷甲硫氨酸（SAM） 同型半胱氨酸（SAH）-而不是蛋氨酸本身-似乎是这两种代谢物的效应代谢物。 对癌细胞增殖和寿命的影响。SAM是主要的细胞甲基供体， SAM/SAH比率通常被认为是细胞甲基化潜力的决定因素。因此 这些代谢物理想地定位于通过特异性甲基化来发出甲硫氨酸水平的信号 事件我们已经确定了RNA和特定蛋白质组上的甲基化事件作为候选物 将甲硫氨酸水平与特定的细胞反应联系起来。该提案的一个目标是确定 通过甲基化控制的关键RNA和蛋白质， 对甲硫氨酸或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， 将甲硫氨酸代谢与细胞增殖和其他细胞功能联系起来。的第二个目标 因此，建议确定这些途径，并开始调查它们如何连接 代谢与细胞生理学在分子水平上的联系。 了解整合蛋氨酸代谢与其他细胞代谢的分子概念 这些功能为治疗癌症和其他年龄相关疾病提供了新的治疗策略。 因此，这项建议的目的是发展分子洞察到一个基本的，迄今为止分子 未经探索的生物过程，具有巨大的治疗开发潜力。