Analysis and Exploitation of Oxygen-Dependent Modification to Ribosomes

核糖体氧依赖性修饰的分析和开发

• 批准号: BB/L004275/1
• 负责人: Christopher Joseph Schofield
• 金额: $ 24.86万
• 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: 2014
• 资助国家: 英国
• 起止时间: 2014 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FL004275%2F1
• 关键词: Analysis; Exploitation; Oxygen; Dependent; Modification

Ribosomes are intracellular machines that make proteins, but they also contain proteins. Recent BBSRC funded work led to the discovery that ribosomal proteins undergo a modification, termed hydroxylation, dependent on atmospheric oxygen at sites of importance for protein biosynthesis. One of the largest classes of antibiotics, e.g. erythromycin, targets ribosomes. Point mutations to ribosomes confer resistance to such antibiotics. Hence it should be possible to develop compounds that selectively target unmodified over modified ribosomes. Tumour cells are often hypoxic so should contain ribosomes that are ales hydroxylated than normal cells. We propose to use Follow on Funding to test synthetically modified antibiotics (guided by ribosome structures) to identify compounds that selectively inhibit unmodified over modified (or vice versa) ribosomes. The results will be used to support patent applications and, if appropriate, to form a spin-out company.

核糖体是制造蛋白质的细胞内机器，但它们也含有蛋白质。最近，BBSRC资助的研究发现，核糖体蛋白在蛋白质生物合成的重要位点上发生了一种称为羟基化的修饰，这种修饰依赖于大气中的氧气。最大种类的抗生素之一，例如红霉素，是针对核糖体的。核糖体的点突变赋予了对这类抗生素的抗性。因此，应该有可能开发出选择性靶向未修饰核糖体的化合物。肿瘤细胞通常是缺氧的，因此应含有比正常细胞羟基化程度低的核糖体。我们建议使用后续资金来测试合成修饰的抗生素（以核糖体结构为指导），以确定选择性抑制未修饰的过修饰（反之亦然）核糖体的化合物。研究结果将用于支持专利申请，如果合适的话，还将成立一家衍生公司。

项目成果

Structure of the ribosomal oxygenase OGFOD1 provides insights into the regio- and stereoselectivity of prolyl hydroxylases.

• DOI: 10.1016/j.str.2015.01.014
• 发表时间: 2015-04-07
• 期刊: STRUCTURE
• 影响因子: 5.7
• 作者: Horita, Shoichiro;Scotti, John S.;Thinnes, Cyrille;Mottaghi-Taromsari, Yousef S.;Thalhammer, Armin;Ge, Wei;Aik, WeiShen;Loenarz, Christoph;Schofield, Christopher J.;McDonough, Michael A.
• 通讯作者: McDonough, Michael A.

Ribosomal oxygenases are structurally conserved from prokaryotes to humans.

• DOI: 10.1038/nature13263
• 发表时间: 2014-06-19
• 期刊: Nature
• 影响因子: 64.8
• 作者: Chowdhury R;Sekirnik R;Brissett NC;Krojer T;Ho CH;Ng SS;Clifton IJ;Ge W;Kershaw NJ;Fox GC;Muniz JRC;Vollmar M;Phillips C;Pilka ES;Kavanagh KL;von Delft F;Oppermann U;McDonough MA;Doherty AJ;Schofield CJ
• 通讯作者: Schofield CJ

Metampicillin is a cyclic aminal produced by reaction of ampicillin with formaldehyde.

• DOI: 10.1038/s41598-020-74990-1
• 发表时间: 2020-10-21
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Reinbold R;John T;Spingardi P;Kawamura A;Schofield CJ;Hopkinson RJ
• 通讯作者: Hopkinson RJ

Protein Hydroxylation Catalyzed by 2-Oxoglutarate-dependent Oxygenases.

• DOI: 10.1074/jbc.r115.662627
• 发表时间: 2015-08-21
• 期刊: The Journal of biological chemistry
• 作者: Markolovic S;Wilkins SE;Schofield CJ
• 通讯作者: Schofield CJ

8-Substituted Pyrido[3,4-d]pyrimidin-4(3H)-one Derivatives As Potent, Cell Permeable, KDM4 (JMJD2) and KDM5 (JARID1) Histone Lysine Demethylase Inhibitors.

• DOI: 10.1021/acs.jmedchem.5b01635
• 发表时间: 2016-02-25
• 期刊: Journal of medicinal chemistry
• 影响因子: 7.3
• 作者: Bavetsias V;Lanigan RM;Ruda GF;Atrash B;McLaughlin MG;Tumber A;Mok NY;Le Bihan YV;Dempster S;Boxall KJ;Jeganathan F;Hatch SB;Savitsky P;Velupillai S;Krojer T;England KS;Sejberg J;Thai C;Donovan A;Pal A;Scozzafava G;Bennett JM;Kawamura A;Johansson C;Szykowska A;Gileadi C;Burgess-Brown NA;von Delft F;Oppermann U;Walters Z;Shipley J;Raynaud FI;Westaway SM;Prinjha RK;Fedorov O;Burke R;Schofield CJ;Westwood IM;Bountra C;Müller S;van Montfort RL;Brennan PE;Blagg J
• 通讯作者: Blagg J