Mechanistic analysis of catalysis and regulation of the fungal proton pump Pma1

真菌质子泵Pma1催化与调控的机理分析

• 批准号: BB/V007653/1
• 负责人: Maike Bublitz
• 金额: $ 64.79万
• 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%2FV007653%2F1
• 关键词: Mechanistic; analysis; catalysis; regulation; fungal

A lipid membrane separates the 'inside' from the 'outside' of each cell in all living organisms. In order to exchange material and information with its surroundings, every cell possesses various transport proteins embedded in its outer membrane. These proteins control what can enter and exit cells, and they are very important gate-keepers between the 'inside' and 'outside' worlds.One large family of such membrane transport proteins literally 'pump' ions across the membrane, thereby building up important imbalances, which are then fuelling other processes, such as nutrient uptake, nerve excitation, or muscle contraction. One such pump, called Pma1, generates a fundamentally important proton gradient in the membranes of all fungi. As a molecular machine that specifically pumps the smallest of all ions - single protons - across the membrane, it is not only interesting in itself, but it is also important from an economic point of view: Pma1 does not exist in humans or animals, and plants have a related but different proton pump. Since fungi cannot survive without Pma1, it could be the target of novel fungicides with a low risk of harmful effects on animals, humans or plants. Such new targets are urgently needed in light of emerging resistances of harmful fungi against those fungicides which are currently in extensive use to protect plants and crops from fungal pests.This research project will reveal how Pma1 transports protons across membranes, by combining state-of-the-art biochemical and biophysical methods to make the molecule itself visible to the human eye. The project will lead to a deeper understanding of the actual proton pumping process, and it will provide the information necessary to develop new fungicides.

脂质膜将所有生物体中每个细胞的“内部”与“外部”分开。为了与周围环境交换物质和信息，每个细胞都拥有嵌入其外膜的各种转运蛋白。这些蛋白质控制着什么可以进入和离开细胞，它们是“内部”和“外部”世界之间非常重要的看门人。此类膜转运蛋白的一大家族实际上是“泵送”离子穿过膜，从而建立重要的不平衡，从而促进其他过程，例如营养吸收、神经兴奋或肌肉收缩。一种这样的泵，称为 Pma1，在所有真菌的细胞膜中产生极其重要的质子梯度。作为一种专门泵送所有离子中最小的离子（单个质子）穿过膜的分子机器，它不仅本身很有趣，而且从经济角度来看也很重要：Pma1 在人类或动物体内不存在，而植物有一个相关但不同的质子泵。由于真菌在没有 Pma1 的情况下无法生存，因此它可能成为新型杀菌剂的目标，对动物、人类或植物产生有害影响的风险较低。鉴于有害真菌对目前广泛使用的杀菌剂产生抗药性，迫切需要此类新靶点。该研究项目将揭示 Pma1 如何跨膜运输质子，通过结合最先进的生物化学和生物物理方法，使分子本身对人眼可见。该项目将加深对实际质子泵送过程的了解，并将提供开发新杀菌剂所需的信息。