Structural, Mechanistic and Functional Studies on Oxgenases

加氧酶的结构、机制和功能研究

• 批准号: BB/V001892/1
• 负责人: Christopher Joseph Schofield
• 金额: $ 100.03万
• 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: 2021
• 资助国家: 英国
• 起止时间: 2021 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FV001892%2F1
• 关键词: Structural; Mechanistic; Functional; Studies; Oxgenases

Proteins are polymers that are crucial to all aspects of life and which are biologically produced by polymerisation of monomeric amino acid precursors. In the early 20th century evidence was reported (by Henry Dakin) that proteins can react with atmospheric oxygen. Later it was found that penicillins are made from a tripeptide (three linked amino acids) by reaction with oxygen. Much more recently it was found that proteins that regulate how humans and other animals respond to limiting oxygen availability (hypoxia) are modified by direct reactions with oxygen, in a manner that decreases their activity. The reaction of these hypoxia inducible factors (HIFs) with oxygen signals for their degradation, so turning on the hypoxic response. The hypoxic response is of massive importance in human biology. If we go to high altitude we make more red blood cells to compensate for the reduced oxygen availability. Red blood cell production is stimulated by increases in the level of a hormone called erythropoietin (EPO), which in turn is increased by the HIFs. EPO is a really important medicine for the treatment of anaemia, but is an expensive protein to make and is not suitable for use by all anaemia sufferers. The hypoxic response is also important in cancer and the development of healthy animal physiology. If HIF degradation can be blocked by a drug EPO levels will increase and in turn red blood cell levels will increase, i.e. there is a new treatment for anaemia. PHD inhibitors have been developed but these are rather blunt instruments.Remarkably, the same family of oxygenases, i.e. enzymes using oxygen for catalysis, includes members that catalyse formation of penicillins from a tripeptide precursor (in effect a tiny protein) and enzymes that are the key regulators of the HIF mediated human hypoxic response - the PHDs. Previous BBSRC work has enabled the characterisation of these two types of oxygenases and shown related enzymes have roles in many other aspects of biology, including lipid metabolism and in the rapidly emerging field of epigenetics. Exactly how the oxygenase proteins interact with oxygen is not, however, well understood. In our new proposed BBSRC work we aim to elucidate the details of this process. In doing so we aim to inform on how dissolved gases interact with proteins in general, something of fundamental interest in biology, including from an evolutionary perspective, but on which there has been relatively little research. The results of our work will inform on how to make new antibiotics and make improved drugs for the treatment of anaemia and other hypoxic related diseases. The work will also enable the UK to remain at the forefront of basic science in research on oxygenases, a field of intense interest (as recognised by the 2019 Nobel prize for studies on the mechanisms of the human hypoxic response to which UK research contributed).

蛋白质是对生命的各个方面都至关重要的聚合物，它是由单体氨基酸前体聚合而成的。世纪早期，亨利·达金（Henry Dakin）报道了蛋白质可以与大气中的氧气发生反应的证据。后来发现青霉素是由三肽（三个连接的氨基酸）与氧反应制成的。最近发现，调节人类和其他动物如何对有限的氧气可用性（缺氧）作出反应的蛋白质通过与氧气的直接反应而改变，从而降低其活性。这些缺氧诱导因子（HIF）与氧信号的反应使其降解，从而开启缺氧反应。缺氧反应在人类生物学中具有重要意义。如果我们去高海拔地区，我们会制造更多的红细胞来弥补减少的氧气供应。红细胞生成是由一种叫做促红细胞生成素（EPO）的激素水平的增加刺激的，而促红细胞生成素又由HIF增加。EPO是治疗贫血的一种非常重要的药物，但它是一种昂贵的蛋白质，不适合所有贫血患者使用。低氧反应在癌症和健康动物生理发育中也很重要。如果HIF降解可以被药物阻断，EPO水平将增加，反过来红细胞水平将增加，即有一种新的治疗贫血的方法。PHD抑制剂已经被开发出来，但这些都是相当钝的工具。值得注意的是，同一个加氧酶家族，即利用氧气进行催化的酶，包括催化从三肽前体（实际上是一种微小的蛋白质）形成青霉素的成员和作为HIF介导的人类缺氧反应的关键调节剂的酶-PHD。先前的BBSRC工作已经能够表征这两种类型的加氧酶，并显示相关的酶在生物学的许多其他方面发挥作用，包括脂质代谢和迅速新兴的表观遗传学领域。然而，加氧酶蛋白质如何与氧相互作用还没有很好的理解。在我们新提出的BBSRC工作中，我们的目标是阐明这一过程的细节。在这样做的过程中，我们的目标是了解溶解气体如何与蛋白质相互作用，这是生物学的基本兴趣，包括从进化的角度来看，但研究相对较少。我们的工作结果将为如何制造新的抗生素和改进治疗贫血和其他缺氧相关疾病的药物提供信息。这项工作还将使英国在加氧酶研究的基础科学领域保持领先地位，这是一个非常感兴趣的领域（2019年诺贝尔奖对英国研究贡献的人类缺氧反应机制的研究）。

项目成果

Conservation of the unusual dimeric JmjC fold of JMJD7 from Drosophila melanogaster to humans.

• DOI: 10.1038/s41598-022-10028-y
• 发表时间: 2022-04-11
• 期刊: SCIENTIFIC REPORTS
• 影响因子: 4.6
• 作者: Chowdhury, Rasheduzzaman;Abboud, Martine, I;Wiley, James;Tumber, Anthony;Markolovic, Suzana;Schofield, Christopher J.
• 通讯作者: Schofield, Christopher J.

Fluorinated derivatives of pyridine-2,4-dicarboxylate are potent inhibitors of human 2-oxoglutarate dependent oxygenases.

• DOI: 10.1016/j.jfluchem.2021.109804
• 发表时间: 2021-07
• 期刊: Journal of fluorine chemistry
• 影响因子: 1.9
• 作者: Brewitz L;Nakashima Y;Tumber A;Salah E;Schofield CJ
• 通讯作者: Schofield CJ

Dioxygen Binding Is Controlled by the Protein Environment in Non‐heme Fe II and 2‐Oxoglutarate Oxygenases: A Study on Histone Demethylase PHF8 and an Ethylene‐Forming Enzyme

非血红素 Fe II 和 2-氧化戊二酸加氧酶中的双氧结合受蛋白质环境控制：组蛋白脱甲基酶 PHF8 和乙烯形成酶的研究

• DOI: 10.1002/chem.202300138
• 发表时间: 2023
• 期刊: Chemistry – A European Journal
• 作者: Chaturvedi, Shobhit S.;Thomas, Midhun George;Rifayee, Simahudeen Bathir Jaber Sathik;White, Walter;Wildey, Jon;Warner, Cait;Schofield, Christopher J.;Hu, Jian;Hausinger, Robert P.;Karabencheva‐Christova, Tatayana G.
• 通讯作者: Karabencheva‐Christova, Tatayana G.

An on-demand, drop-on-drop method for studying enzyme catalysis by serial crystallography.

• DOI: 10.1038/s41467-021-24757-7
• 发表时间: 2021-07-22
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Butryn A;Simon PS;Aller P;Hinchliffe P;Massad RN;Leen G;Tooke CL;Bogacz I;Kim IS;Bhowmick A;Brewster AS;Devenish NE;Brem J;Kamps JJAG;Lang PA;Rabe P;Axford D;Beale JH;Davy B;Ebrahim A;Orlans J;Storm SLS;Zhou T;Owada S;Tanaka R;Tono K;Evans G;Owen RL;Houle FA;Sauter NK;Schofield CJ;Spencer J;Yachandra VK;Yano J;Kern JF;Orville AM
• 通讯作者: Orville AM

Structural analysis of the 2-oxoglutarate binding site of the circadian rhythm linked oxygenase JMJD5.

• DOI: 10.1038/s41598-022-24154-0
• 发表时间: 2022-11-30
• 期刊: SCIENTIFIC REPORTS
• 影响因子: 4.6
• 作者: Islam, Md Saiful;Markoulides, Marios;Chowdhury, Rasheduzzaman;Schofield, Christopher J.
• 通讯作者: Schofield, Christopher J.