Functional assignments on human oxygenases

人类氧酶的功能分配

• 批准号: BB/D011523/1
• 负责人: Christopher Joseph Schofield
• 金额: $ 91.73万
• 依托单位: University of Oxford
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2006
• 资助国家: 英国
• 起止时间: 2006 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FD011523%2F1
• 关键词: Functional; assignments; human; oxygenases

Regulating oxygen delivery to cells is a problem for all aerobic organisms ranging from bacteria to humans. In mammals, the lungs, heart and blood are all devoted to this task, and human diseases (such as strokes, heart attacks and anaemia) often involve damage to organs by low oxygen levels (hypoxia). Basic science work supported by the BBSRC has provided insights into how cells 'sense' and respond to hypoxia. The work has helped to identify a set of 'oxygenases' (a type of enzyme that catalyses the incorporation of atmospheric oxygen into their substrates) that catalyse the addition of oxygen atoms to a protein called hypoxia inducible factor (HIF), so called because its level is raised under low oxygen concentrations. HIF is important as it occurs in a very wide range of organisms including insects, worms and humans; it enables the expression of a range of genes that work to help the organism overcome the challenge of hypoxia. In humans these genes enable a response to hypoxia and include those involved in blood vessel and red blood cell formation. Addition of oxygen to HIF stops its ability to enable the expression of the genes involved in the hypoxic response. When there is sufficient oxygen the oxygenases can catalyse its addition to HIF, but when oxygen levels fall HIF is no longer modified and it is free to enable expression of the genes involved in the hypoxic response. We hope that the results of this work will result in new treatments for diseases involving the cardiovascular system. By inhibiting the HIF oxygenases with small molecule drugs, it should be possible to improve the body's natural defence against damage from low oxygen concentrations. However to do this safely without causing side effects will require more knowledge of other human oxygenases, that have been revealed by analysis of the human genome. The work on the HIF system has raised questions as to the extent of the role of oxygenases in controlling the expression of genes in other pathways and indeed biology as a whole. This proposal seeks to go some way towards addressing these questions by studying human oxygenases, some of which are known to be biomedicinally important from work at the physiological level but for which there is little or no data in terms of their actual substrates and roles at a biochemical level. There are technical problems in working with human cells compared to, for example, those from microorganisms. However, we have chosen to work with human enzymes, in part, because the worldwide efforts in genome sequencing and other large scale projects studying the proteins present in human cells have provided a resource we can utilise to help assign biochemical roles for the oxygenases, and, in part, because we hope that the work will be useful in the development of new therapies based on a better understanding of human metabolism.

调节氧气输送到细胞是从细菌到人类的所有需氧生物的问题。在哺乳动物中，肺、心脏和血液都致力于这一任务，而人类疾病（如中风、心脏病发作和贫血）往往涉及低氧水平（缺氧）对器官的损害。由BBSRC支持的基础科学工作为细胞如何“感知”和响应缺氧提供了见解。这项工作有助于确定一组“加氧酶”（一种催化将大气中的氧结合到其底物中的酶），该酶催化将氧原子添加到一种称为缺氧诱导因子（HIF）的蛋白质中，之所以这样称呼是因为它的水平在低氧浓度下升高。HIF是重要的，因为它发生在非常广泛的生物体中，包括昆虫，蠕虫和人类;它使一系列基因的表达能够帮助生物体克服缺氧的挑战。在人类中，这些基因能够对缺氧做出反应，包括那些参与血管和红细胞形成的基因。向HIF中加入氧会阻止其表达参与低氧反应的基因的能力。当有足够的氧时，加氧酶可以催化其添加到HIF中，但是当氧水平下降时，HIF不再被修饰，并且它可以自由地使参与低氧反应的基因表达。我们希望这项工作的结果将导致涉及心血管系统疾病的新治疗方法。通过用小分子药物抑制HIF加氧酶，应该可以改善身体对低氧浓度损害的自然防御。然而，要安全地做到这一点，而不引起副作用，将需要更多的知识，其他人类加氧酶，已揭示了人类基因组的分析。对HIF系统的研究提出了加氧酶在控制其他途径中的基因表达以及整个生物学中的作用程度的问题。该提案旨在通过研究人类加氧酶来解决这些问题，其中一些加氧酶在生理水平的工作中具有生物医学重要性，但关于其实际底物和作用的数据很少或根本没有生化水平。例如，与来自微生物的细胞相比，使用人类细胞存在技术问题。然而，我们选择了与人类酶合作，部分原因是全球在基因组测序和其他研究人类细胞中存在的蛋白质的大规模项目方面的努力提供了一种资源，我们可以利用它来帮助分配加氧酶的生化作用，部分原因是我们希望这项工作将有助于开发基于更好地了解人类代谢的新疗法。

项目成果

The obesity-associated FTO gene encodes a 2-oxoglutarate-dependent nucleic acid demethylase.

• DOI: 10.1126/science.1151710
• 发表时间: 2007-11-30
• 期刊: Science (New York, N.Y.)
• 作者: Gerken T;Girard CA;Tung YC;Webby CJ;Saudek V;Hewitson KS;Yeo GS;McDonough MA;Cunliffe S;McNeill LA;Galvanovskis J;Rorsman P;Robins P;Prieur X;Coll AP;Ma M;Jovanovic Z;Farooqi IS;Sedgwick B;Barroso I;Lindahl T;Ponting CP;Ashcroft FM;O'Rahilly S;Schofield CJ
• 通讯作者: Schofield CJ

PTP1B controls non-mitochondrial oxygen consumption by regulating RNF213 to promote tumour survival during hypoxia.

• DOI: 10.1038/ncb3376
• 发表时间: 2016-07
• 期刊: Nature cell biology
• 影响因子: 21.3
• 作者: Banh RS;Iorio C;Marcotte R;Xu Y;Cojocari D;Rahman AA;Pawling J;Zhang W;Sinha A;Rose CM;Isasa M;Zhang S;Wu R;Virtanen C;Hitomi T;Habu T;Sidhu SS;Koizumi A;Wilkins SE;Kislinger T;Gygi SP;Schofield CJ;Dennis JW;Wouters BG;Neel BG
• 通讯作者: Neel BG

Oxygenase-catalyzed ribosome hydroxylation occurs in prokaryotes and humans.

• DOI: 10.1038/nchembio.1093
• 发表时间: 2012-12
• 期刊: Nature chemical biology
• 影响因子: 14.8
• 作者: Ge W;Wolf A;Feng T;Ho CH;Sekirnik R;Zayer A;Granatino N;Cockman ME;Loenarz C;Loik ND;Hardy AP;Claridge TDW;Hamed RB;Chowdhury R;Gong L;Robinson CV;Trudgian DC;Jiang M;Mackeen MM;Mccullagh JS;Gordiyenko Y;Thalhammer A;Yamamoto A;Yang M;Liu-Yi P;Zhang Z;Schmidt-Zachmann M;Kessler BM;Ratcliffe PJ;Preston GM;Coleman ML;Schofield CJ
• 通讯作者: Schofield CJ

Pseudomonas expression of an oxygen sensing prolyl hydroxylase homologue regulates neutrophil host responses in vitro and in vivo.

• DOI: 10.12688/wellcomeopenres.12871.1
• 发表时间: 2017
• 期刊: Wellcome open research
• 作者: Dickinson RS;Murphy F;Doherty C;Williams S;Mirchandani A;Willson J;Scotti JS;Preston G;Schofield CJ;Whyte MKB;Walmsley SR
• 通讯作者: Walmsley SR

Tuning the Transcriptional Response to Hypoxia by Inhibiting Hypoxia-inducible Factor (HIF) Prolyl and Asparaginyl Hydroxylases.

• DOI: 10.1074/jbc.m116.749291
• 发表时间: 2016-09-23
• 期刊: The Journal of biological chemistry
• 作者: Chan MC;Ilott NE;Schödel J;Sims D;Tumber A;Lippl K;Mole DR;Pugh CW;Ratcliffe PJ;Ponting CP;Schofield CJ
• 通讯作者: Schofield CJ