RapidFire Enhancement of Mass Spectrometry Capability Across the Biosciences

RapidFire 增强整个生物科学领域的质谱分析能力

• 批准号: BB/R000344/1
• 负责人: James McCullagh
• 金额: $ 75.66万
• 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: 2017
• 资助国家: 英国
• 起止时间: 2017 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FR000344%2F1
• 关键词: RapidFire; Enhancement; Mass; Spectrometry; Capability

A major current challenge in biological science is to capitalise on the wealth of genomic information arising from DNA sequencing, to characterise the function and structure of DNA-encoded proteins. However, while genome sequencing has become very rapid, no methods currently exist which can experimentally determine the molecular details of the gene-products on a comparable timescale. As such the gulf between our understanding of what proteins are present in an organism and how they orchestrate the cellular processes necessary to life is ever increasing. Mass spectrometry (MS) is a method that has revolutionised the experimental identification of proteins and quantification of their cellular abundances. In Oxford we have pioneered a number of MS-based approaches to determine the structures, interactions, and dynamics of proteins, and to elucidate their biochemical roles in cells and whole organisms. However, we now need technology that can help analyse and exploit function at a rate comparable to that of data generated by the genomic revolution. As a step towards this, we propose to acquire a state-of-the-art RapidFire MS system to enable a step-change in the rate of our ability to accurately identify, analyse and quantify function in biological processes.Specifically, the RapidFire 365 coupled to a high resolution iFunnel6550 QTof MS, will enable multiple current and future BBSRC researchers to dramatically increase the throughput at which we can screen biological reactions by over two orders of magnitude, including the analysis of biological reactions in real time. The dramatic increase in speed will revolutionise our ability to obtain functional assignments and identify ways to manipulate biological function on a biochemical level. The new instrumentation will be integrated into dedicated laboratories in the Department of Chemistry in Oxford, providing new capabilities within the context of a carefully selected and comprehensive collection of instruments aimed at applying MS to the frontiers of chemical biology. The RapidFire MS system will be genuinely multi-user, enabling BBSRC-funded research by a large number of research groups in Oxford and the UK, through well-defined access routes overseen by experienced staff. The instruments will support research projects spanning a range of BBSRC strategic research priority areas, and will become an integrated piece of equipment in the Interdisciplinary Biosciences Doctoral Training Programme, thus making it readily available to researchers at other sites within this programme including Oxford Brookes University and the Diamond Light Source.

生物科学当前的一个主要挑战是利用DNA测序所产生的丰富的基因组信息，来分析DNA编码蛋白质的功能和结构。然而，虽然基因组测序已经变得非常迅速，但目前还不存在可以在可比较的时间尺度上通过实验确定基因产物的分子细节的方法。因此，我们对生物体中存在哪些蛋白质的理解与它们如何协调生命所需的细胞过程之间的鸿沟正在不断扩大。质谱法（MS）是一种彻底改变蛋白质实验鉴定及其细胞丰度定量的方法。在牛津大学，我们开创了许多基于MS的方法来确定蛋白质的结构，相互作用和动力学，并阐明它们在细胞和整个生物体中的生化作用。然而，我们现在需要能够帮助分析和利用功能的技术，其速度可以与基因组革命产生的数据相媲美。作为实现这一目标的一步，我们建议获得一个最先进的RapidFire MS系统，以使我们能够准确识别，分析和量化生物过程中的功能的能力发生阶跃变化。具体来说，RapidFire 365与高分辨率iFunnel6550 QTof MS相结合，将使多个当前和未来的BBSRC研究人员能够将我们筛选生物反应的通量大幅提高两个数量级以上，包括对真实的生物反应的分析。速度的大幅提高将彻底改变我们获得功能分配的能力，并确定在生化水平上操纵生物功能的方法。新仪器将被集成到牛津大学化学系的专用实验室中，在精心挑选和全面收集仪器的背景下提供新的功能，旨在将MS应用于化学生物学的前沿。RapidFire MS系统将是真正的多用户，通过经验丰富的工作人员监督的明确的访问路线，使牛津和英国的大量研究小组能够进行BBSRC资助的研究。这些仪器将支持跨越一系列BBSRC战略研究优先领域的研究项目，并将成为跨学科生物科学博士培训计划的一个集成设备，从而使其随时可供该计划内其他地点的研究人员使用，包括牛津布鲁克斯大学和钻石光源。

项目成果

5-Substituted Pyridine-2,4-dicarboxylate Derivatives Have Potential for Selective Inhibition of Human Jumonji-C Domain-Containing Protein 5.

• DOI: 10.1021/acs.jmedchem.3c01114
• 发表时间: 2023-08-10
• 期刊: JOURNAL OF MEDICINAL CHEMISTRY
• 影响因子: 7.3
• 作者: Brewitz, Lennart;Nakashima, Yu;Piasecka, Sonia K.;Salah, Eidarus;Fletcher, Sally C.;Tumber, Anthony;Corner, Thomas P.;Kennedy, Tristan J.;Fiorini, Giorgia;Thalhammer, Armin;Christensen, Kirsten E.;Coleman, Mathew L.;Schofield, Christopher J.
• 通讯作者: Schofield, Christopher J.

Human Oxygenase Variants Employing a Single Protein Fe II Ligand Are Catalytically Active

采用单一蛋白质 Fe II 配体的人类加氧酶变体具有催化活性

• DOI: 10.1002/ange.202103711
• 发表时间: 2021
• 期刊: Angewandte Chemie
• 作者: Brasnett A

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

Alkyne Derivatives of SARS-CoV-2 Main Protease Inhibitors Including Nirmatrelvir Inhibit by Reacting Covalently with the Nucleophilic Cysteine.

SARS-COV-2主要蛋白酶抑制剂（包括Nirmatrelvir）的碱衍生物通过与亲核性半胱氨酸的共价反应来抑制。

• DOI: 10.1021/acs.jmedchem.2c01627
• 发表时间: 2023-02-23
• 期刊: JOURNAL OF MEDICINAL CHEMISTRY
• 影响因子: 7.3
• 作者: Brewitz, Lennart;Dumjahn, Leo;Zhao, Yilin;Owen, C. David;Laidlaw, Stephen M.;Malla, Tika R.;Nguyen, Dung;Lukacik, Petra;Salah, Eidarus;Crawshaw, Adam D.;Warren, Anna J.;Trincao, Jose;Strain-Damerell, Claire;Carroll, Miles W.;Walsh, Martin A.;Schofield, Christopher J.
• 通讯作者: Schofield, Christopher J.

Combined proteomic and biochemical analyses redefine the consensus sequence requirement for epidermal growth factor-like domain hydroxylation.

• DOI: 10.1016/j.jbc.2022.102129
• 发表时间: 2022-08
• 期刊: JOURNAL OF BIOLOGICAL CHEMISTRY
• 影响因子: 4.8
• 作者: Brewitz, Lennart;Onisko, Bruce C.;Schofield, Christopher J.
• 通讯作者: Schofield, Christopher J.