IMPC: Investigation into the function of pyrroline 5-carboxylate reductase 1 (PYCR1) in metabolic homeostasis

IMPC：吡咯啉 5-羧酸还原酶 1 (PYCR1) 在代谢稳态中的功能研究

• 批准号: MR/R01468X/1
• 负责人: Daniel Tennant
• 金额: $ 4.01万
• 依托单位: University of Birmingham
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2018
• 资助国家: 英国
• 起止时间: 2018 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FR01468X%2F1
• 关键词: IMPC; Investigation; into; function; pyrroline

The metabolism of cells is tightly controlled so that nutrients taken up from the outside are used efficiently, and only when necessary. This level of control requires checks and balances that link different metabolic activities - for example the metabolism of sugars and amino acids - ensuring normal cell function. One key aspect of metabolism that is critical for normal cell function is known as redox homeostasis - the balance of pro- and anti-oxidants. An aberrant redox status in a cell can lead to its malfunction and drive changes that may result in disease. Some diseases known to be linked to changes in redox homeostasis are cancer, diabetes and chronic inflammation. We have recently discovered that our understanding of how the enzyme known as pyrroline 5-carboxylate reductase 1 (PYCR1) functions, may be incorrect. This enzyme is responsible for making an amino acid called proline, but in doing so, it influences the redox state of the cell. Although we've previously thought that the main function of this enzyme was to make proline, it may actually be to react to changes in cell redox to try and keep the metabolism of the cell healthy.This proposal will provide the first physiological information to support our hypothesis - that PYCR1 is a critical enzyme in the response to changes in the redox environment of cell. The data that comes out of this research will provide the building blocks - both data and animal model - for a bigger grant application to investigate this hypothesis more fully.

细胞的新陈代谢受到严格控制，因此从外部摄取的营养物质仅在必要时才被有效利用。这种水平的控制需要检查和平衡，连接不同的代谢活动-例如糖和氨基酸的代谢-确保正常的细胞功能。新陈代谢的一个关键方面是对正常细胞功能至关重要的，被称为氧化还原稳态-前氧化剂和抗氧化剂的平衡。细胞中异常的氧化还原状态可能导致其功能障碍并驱动可能导致疾病的变化。一些已知与氧化还原稳态变化有关的疾病是癌症、糖尿病和慢性炎症。我们最近发现，我们对吡咯啉5-羧酸还原酶1（PYCR 1）功能的理解可能是不正确的。这种酶负责制造一种名为脯氨酸的氨基酸，但在这样做的过程中，它会影响细胞的氧化还原状态。虽然我们以前认为这种酶的主要功能是产生脯氨酸，但它实际上可能是对细胞氧化还原的变化做出反应，试图保持细胞的代谢健康。这一提议将提供第一个生理信息来支持我们的假设-PYCR 1是细胞氧化还原环境变化的关键酶。从这项研究中得出的数据将为更大的拨款申请提供基础-数据和动物模型-以更全面地调查这一假设。

项目成果

Proline synthesis through PYCR1 is required to support cancer cell proliferation and survival in oxygen-limiting conditions.

• DOI: 10.1016/j.celrep.2022.110320
• 发表时间: 2022-02-01
• 期刊: Cell reports
• 影响因子: 8.8
• 作者: Westbrook RL;Bridges E;Roberts J;Escribano-Gonzalez C;Eales KL;Vettore LA;Walker PD;Vera-Siguenza E;Rana H;Cuozzo F;Eskla KL;Vellama H;Shaaban A;Nixon C;Luuk H;Lavery GG;Hodson DJ;Harris AL;Tennant DA
• 通讯作者: Tennant DA