Capturing Natural Product Factories in Action

捕捉正在行动的天然产品工厂

• 批准号: 2879768
• 金额: --
• 依托单位: University of Bristol
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2879768
• 关键词: Capturing; Natural; Product; Factories; Action

Polyketides are biosynthesised by large, multi-modular polypeptides known as polyketide synthases (PKS). These contain diverse catalytic domains, that are programmed to function in a highly controlled fashion. Nature employs a range of strategies to introduce structural diversity into polyketides with exquisite control of regio- and stereochemistry. One such example is the introduction of alkyl chains at the electrophilic beta-position of the growing polyketide - so called beta-branching. This process is under the control of a set of enzymes known collectively as a 3-hydroxy-3-methylglutaryl synthase (HMGS) cassette, usually yielding a beta-methyl branched alpha,beta-unsaturated product. Bongkrekic acid is one example of a polyketide which contains two beta-branches. One of these, the carboxymethyl beta-branch, appears to omit the final ECH2 (BonI)-catalysed decarboxylation. It is not currently known how this is controlled. Utilising an in vitro NMR assay, we aim to monitor [13C]-labelled acyl carrier protein (ACP)-bound intermediates, in real time, as they proceed through an enzyme cascade. We aim to synthesise [13C]-labelled ACP-bound substrates which incorporate a sub-section of bongkrekic acid and apply NMR to monitor the fate of this intermediate. Bongkrekic acid is just one of many examples of beta-branching in polyketides and the development and implementation of this NMR assay could be applied to a variety of systems.

聚酮化合物由称为聚酮化合物酶（PKS）的大的多模块多肽生物合成。这些包含不同的催化结构域，这些结构域被编程为以高度受控的方式发挥作用。大自然采用了一系列的策略，以引入结构多样性的聚酮化合物与精致的控制区域和立体化学。 一个这样的例子是在生长的聚酮化合物的亲电β-位置引入烷基链-所谓的β-分支。该过程在统称为3-羟基-3-甲基戊二酰合酶（HMGS）盒的一组酶的控制下，通常产生β-甲基支链α，β-不饱和产物。Bongkrekic酸是含有两个β-支链的聚酮化合物的一个实例。其中之一，羧甲基β-分支，似乎省略了最终的ECH 2（BonI）催化脱羧。目前尚不清楚这是如何控制的。利用体外NMR分析，我们的目标是监测[13 C]-标记的酰基载体蛋白（ACP）结合的中间体，在真实的时间，因为它们通过酶级联进行。我们的目标是合成[13 C]-标记的ACP结合底物，其中包含一个子部分的bongkrekic酸，并应用NMR监测这种中间体的命运。Bongkrekic酸只是聚酮化合物中β-分支的许多例子之一，这种NMR测定的开发和实施可以应用于各种系统。