The role of intermediate binding in Type I and Type II acyl carrier proteins
I 型和 II 型酰基载体蛋白中中间结合的作用
基本信息
- 批准号:BB/F014570/1
- 负责人:
- 金额:$ 43.56万
- 依托单位:
- 依托单位国家:英国
- 项目类别:Research Grant
- 财政年份:2008
- 资助国家:英国
- 起止时间:2008 至 无数据
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
Natural products play an enormous role in human and veterinary medicine providing a valuable source of antibiotics, antifungals and anticancer agents. The widespread use of, particularly, broad-spectrum antibiotics at doses aimed at disease prevention rather than the treatment of infections has meant that many organisms have developed resistance to these drugs. These include bacteria, which cause serious infections in hospitalised patients despite government attempts to clean up wards and improve hygiene; bacteria that cause respiratory diseases such as pneumonia and tuberculosis; food-borne pathogens and sexually transmitted organisms. A significant research priority is to develop new drugs in this constant to and fro battle, which can deal with these resistant organisms. To combat this we are studying the bacteria and fungi that provide these valuable sources of natural products. Intense research over the last 30 years has greatly increased our understanding of how these organisms make these molecules. It turns out not to be simple. It is now known that there are vastly complex arrays of enzymes (complex biological molecules) that perform a series of programmed building steps to produce the final molecule. This can be likened to a production line where each element has a particular job to do and must do it in the correct order and with very high precision. Sometimes these arrays are arranged as one large assembly, in others they are present as separate components that somehow find each other as required. Despite these different architectures, each of these assembly lines features a common component, a so called Acyl Carrier Protein or ACP. This protein is an intelligent chip that must carry the molecule being processed to each enzyme and in some cases may shield it from the surrounding environment. We want to understand how this protein works, how it recognises its partners and how it may protect the molecule it is carrying. To do this, we use a technique called Nuclear Magnetic Resonance spectroscopy (NMR) that works with aqueous solutions of the proteins and tells us their shape. We combine this technique with our ability to modify the ACP with molecules that resemble the natural molecules it carries. We wish to understand if it actively uses the molecule it carries to change its shape so it then fits correctly into the correct next enzyme in the synthetic sequence. We will look at a number of different ACPs that carry different types of molecules and which have a varying need for molecular recognition and product stabilisation. We have also discovered that some assemblies use more than one ACP at critical junctions and these may help relieve bottlenecks in the biosynthetic sequence. Our understanding of these ACPs is very limited so we wish to begin to understand how 2 or 3 ACPs might fit together and cooperate with one another.
天然产物在人类和兽医医学中发挥着巨大作用,提供了抗生素、抗真菌和抗癌药物的宝贵来源。特别是广谱抗生素的广泛使用,其剂量旨在预防疾病而不是治疗感染,这意味着许多生物体已经对这些药物产生了耐药性。其中包括细菌,尽管政府试图清理病房并改善卫生状况,但细菌仍会导致住院患者严重感染;引起肺炎和肺结核等呼吸道疾病的细菌;食源性病原体和性传播微生物。一个重要的研究重点是在这场持续不断的战斗中开发新的药物,以应对这些耐药生物。为了解决这个问题,我们正在研究提供这些宝贵的天然产物来源的细菌和真菌。过去 30 年的深入研究极大地加深了我们对这些生物体如何制造这些分子的了解。事实证明并不简单。现在已知存在极其复杂的酶阵列(复杂的生物分子),它们执行一系列编程的构建步骤来产生最终的分子。这可以比作一条生产线,其中每个元件都有特定的工作要做,并且必须以正确的顺序和非常高的精度完成。有时,这些阵列被排列为一个大型组件,而在其他情况下,它们作为单独的组件出现,并以某种方式根据需要找到彼此。尽管架构不同,但每条装配线都具有共同的成分,即所谓的酰基载体蛋白或 ACP。这种蛋白质是一种智能芯片,必须将正在处理的分子携带到每种酶上,并且在某些情况下可以保护其免受周围环境的影响。我们想了解这种蛋白质是如何工作的,它如何识别它的伙伴,以及它如何保护它所携带的分子。为此,我们使用一种称为核磁共振波谱 (NMR) 的技术,该技术可处理蛋白质的水溶液并告诉我们它们的形状。我们将这项技术与我们用类似于其携带的天然分子的分子修饰 ACP 的能力相结合。我们希望了解它是否主动使用其携带的分子来改变其形状,以便它正确地适合合成序列中正确的下一个酶。我们将研究许多不同的 ACP,它们携带不同类型的分子,并且对分子识别和产品稳定性有不同的需求。我们还发现一些组件在关键连接处使用多个 ACP,这些可能有助于缓解生物合成序列中的瓶颈。我们对这些 ACP 的了解非常有限,因此我们希望开始了解 2 或 3 个 ACP 如何组合在一起并相互合作。
项目成果
期刊论文数量(9)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
The Path to Actinorhodin: Regio- and Stereoselective Ketone Reduction by a Type II Polyketide Ketoreductase Revealed in Atomistic Detail
放线菌素之路:通过原子细节揭示 II 型聚酮化合物酮还原酶的区域选择性和立体选择性酮还原
- DOI:10.26434/chemrxiv-2021-wdlmj-v2
- 发表时间:2022
- 期刊:
- 影响因子:0
- 作者:Serapian S
- 通讯作者:Serapian S
Recognition of extended linear and cyclised polyketide mimics by a type II acyl carrier protein.
- DOI:10.1039/c5sc03864b
- 发表时间:2016-03-01
- 期刊:
- 影响因子:8.4
- 作者:Dong X;Bailey CD;Williams C;Crosby J;Simpson TJ;Willis CL;Crump MP
- 通讯作者:Crump MP
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Matthew Crump其他文献
Matthew Crump的其他文献
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{{ truncateString('Matthew Crump', 18)}}的其他基金
New tools for elucidating natural product biosynthesis in-situ at atomic resolution
以原子分辨率原位阐明天然产物生物合成的新工具
- 批准号:
BB/W008823/1 - 财政年份:2022
- 资助金额:
$ 43.56万 - 项目类别:
Research Grant
A globally unique 19F, 13C, 15N NMR system to enable frontier bioscience
全球独一无二的 19F、13C、15N NMR 系统,助力前沿生物科学
- 批准号:
BB/V019163/1 - 财政年份:2021
- 资助金额:
$ 43.56万 - 项目类别:
Research Grant
Acquisition of hierarchical control in skilled action sequencing
在熟练的动作排序中获得分层控制
- 批准号:
1353360 - 财政年份:2014
- 资助金额:
$ 43.56万 - 项目类别:
Continuing Grant
Protein-ligand coupled motions in DHFR catalysis
DHFR 催化中的蛋白质-配体耦合运动
- 批准号:
BB/J005398/1 - 财政年份:2012
- 资助金额:
$ 43.56万 - 项目类别:
Research Grant
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