The roles of transporters in the human metabolic network

转运蛋白在人体代谢网络中的作用

基本信息

批准号：
BB/P009042/1
负责人：
Douglas Kell
金额：
$ 71.87万
依托单位：
University of Manchester
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%2FP009042%2F1
关键词：
roles transporters human metabolic network

项目摘要

When you eat a foodstuff or a pill (i.e. a pharmaceutical drug) it is important that the relevant molecules go to the places where they will be of most benefit. How nutrients and drugs are absorbed and distributed (and eventually excreted) is thus a topic of high importance. When it goes wrong in the case of drugs they may not work properly or may even be toxic; this latter is known as an Adverse Drug Reaction, and they account for more than 5% of hospital admissions. Cells are bounded by cell membranes, whose job it is to stop them letting in any old rubbish. Instead, these membranes contain proteins called transporters that serve to ferry small molecules into and out of cells as part of the day-to-day reactions (metabolism) that keep us alive. Such transporters account for fully one third of the gene products involved in these biochemical networks. It turns out in general terms that, since all they recognise is a molecule, without knowing its 'purpose' (nutrient, drug, vitamin, etc), just these same transporters are involved in transporting nutrients, vitamins and pharmaceutical drugs into cells; the problem is that we do not tend to know which transporters transport which substances, and this correlation-based assessment is what we wish to find out here.To do this we shall study how transporter levels and the extent of small molecule uptake vary together between different cells and tissues; given enough of these paired measurements we can work out which changes in which transporters best account for the changes in small molecule uptake, including molecules not used in the learning phase, and can then test directly that they do indeed transport the molecules we claim. Because the transporter levels naturally vary between tissues they must naturally be controlled, and several substances (such as vitamin D) are known to affect these levels dramatically. This means that we can expect to be able to modulate the expression of transporters and different tissues by adding a second molecule (a so-called 'binary weapon'), and thereby 'force' particular substances to go only to those tissues. We shall test this by adding a library of small artificial (man-made) molecules (so-called 'fragments') and seeing which of them can do this (at least to some degree). Computer methods help us to find larger and more potent molecules that possess these same fragment signatures and that would therefore be predicted to have the desired targeting effects. Importantly, we shall curate all of the data in a web-accessible database.

当您吃食物或药丸（即药物）时，相关分子要去它们最有益的地方很重要。因此，营养素和药物如何被吸收和分布（最终排出）是一个非常重要的话题。当毒品出现问题时，它们可能无法正常工作，甚至可能有毒；后者被称为不良药物反应，它们占住院的5％以上。细胞受细胞膜的界定，其工作是阻止它们放入任何旧垃圾。取而代之的是，这些膜含有称为转运蛋白的蛋白质，这些蛋白质可作为日常反应（代谢）的一部分，将小分子运送到细胞中，从而使我们活着。这些转运蛋白完全解释了这些生化网络中涉及的基因产物的三分之一。事实证明，由于他们所识别的只是一个分子，而不知道其“目的”（营养，药物，维生素等），因此这些相同的转运蛋白参与将营养素，维生素和药物运输到细胞中。问题在于，我们不倾向于知道哪种转运蛋白运输哪种物质，而基于相关的评估是我们希望在这里找到的。为此，我们将研究转运蛋白水平和小分子吸收的程度如何在不同的细胞和组织；在这些配对的测量中，我们可以弄清楚哪些变化哪些变化最能说明小分子摄取的变化，包括在学习阶段未使用的分子，然后可以直接测试它们确实运输了我们声称的分子。由于它们的转运蛋白水平自然会自然地控制它们，因此已知几种物质（例如维生素D）会极大地影响这些水平。这意味着我们可以期望能够通过添加第二个分子（一种所谓的“二进制武器”）来调节转运蛋白和不同组织的表达，从而仅将“力”特定物质用于这些组织。我们将通过添加一个小型人造（人造）分子（所谓的“碎片”）来测试这一点，并查看其中哪个可以做到这一点（至少在某种程度上）。计算机方法可以帮助我们找到具有相同片段特征的更大，更有效的分子，因此可以预测具有所需的靶向效应。重要的是，我们将在可访问的数据库中策划所有数据。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Energetic Evolution of Cellular Transportomes

细胞转运体的能量进化

DOI：
10.1101/218396
发表时间：
2017
期刊：
影响因子：
0
作者：
Darbani B
通讯作者：
Darbani B

Additional file 1: of Energetic evolution of cellular Transportomes

附加文件1：细胞运输组的能量进化

DOI：
10.6084/m9.figshare.6395714
发表时间：
2018
期刊：
影响因子：
0
作者：
Behrooz Darbani
通讯作者：
Behrooz Darbani

An Overview of Cell-Based Assay Platforms for the Solute Carrier Family of Transporters.

DOI：
10.3389/fphar.2021.722889
发表时间：
2021
期刊：
Frontiers in pharmacology
影响因子：
5.6
作者：
Dvorak V;Wiedmer T;Ingles-Prieto A;Altermatt P;Batoulis H;Bärenz F;Bender E;Digles D;Dürrenberger F;Heitman LH;IJzerman AP;Kell DB;Kickinger S;Körzö D;Leippe P;Licher T;Manolova V;Rizzetto R;Sassone F;Scarabottolo L;Schlessinger A;Schneider V;Sijben HJ;Steck AL;Sundström H;Tremolada S;Wilhelm M;Wright Muelas M;Zindel D;Steppan CM;Superti-Furga G
通讯作者：
Superti-Furga G

Control of metabolite efflux in microbial cell factories: Current advances and future prospects