Synthetic biology approaches to construct metal analogues of vitamin B12 to act as anti-microbial and imaging agents for health applications.

利用合成生物学方法构建维生素 B12 的金属类似物，作为健康应用的抗菌剂和显像剂。

• 批准号: 2881504
• 金额: --
• 依托单位: University of Southampton
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2881504
• 关键词: Synthetic; biology; approaches; construct; metal; Synthetic; biology; approaches; construct; metal

Vitamin B12 (cobalamin) is an essential micronutrient whose synthesis is restricted to only certain bacteria. It is one of the most complex molecules found in Nature, consisting of a cobalt-containing corrin ring and a lower base attached via the nucleotide loop. The biological activity of the molecule is dependent on the properties of the metal ion at its centre.We have successfully prepared several metal analogues of cobalamin (Rh, Zn and Ni). This was achieved using a novel approach consisting of an engineered bacterial strain which can produce a metal-free intermediate, hydrogenobyric acid (Hby), and then subsequent biochemical and chemical steps to complete the synthesis and produce the desired analogues. While the system works well, we are looking to optomise/simplify the synthesis by further engineering the E. coli strain, using genes from Chromatium vinosum which is known to produce cobalt-free cobalamin under specific conditions.We have determined that the rhodium analogue is an inhibitor of B12-dependent processes, but we currently know very little about the biological activity of the metal analogues. We wish to expand our knowledge in this area by looking at the cellular uptake and trafficking of the analogues, their effect on B12-dependent enzymes and processes, and document any antimicrobial/anticancer activity present. The ability to replace the metal ion also opens the possibility of creating unique medical imaging agents for positron emission tomography (PET) which could be used in cancer diagnosis.The aim of this project is to:1. Synthesise a range of metal analogues of cobalamin (Cu, Rh, Zn and Ni).2. Investigate the biological properties of the metal analogues (eg. vitamin uptake/transport, enzyme inhibition, antimicrobial/anticancer agents).3. Engineer an E. coli strain capable of producing cobalt-free cobalamin (hydrogenobalamin).

维生素B12（钴胺素）是必需的微量营养素，其合成仅限于某些细菌。它是自然界中发现的最复杂的分子之一，由含钴的Corrin环和通过核苷酸环连接的较低碱基组成。该分子的生物学活性取决于金属离子在其中心的性质。我们成功制备了钴胺素的几种金属类似物（RH，Zn和Ni）。这是使用由工程细菌菌株组成的新型方法来实现的，该方法可以产生无金属中间体，氢气酸（HBY），然后随后采用生化和化学步骤来完成合成并产生所需的类似物。虽然该系统运行良好，但我们希望通过进一步工程大肠杆菌菌株进行验光/简化合成，该基因使用Vinosum染色体中的基因，该基因在特定条件下可产生无钴的钴胺素。我们已经确定，我们已经确定了阳极类似物是B12依赖的过程的抑制剂，但我们目前了解到对该金属型拟型型的生物造型活动。我们希望通过查看类似物的细胞摄取和贩运，它们对B12依赖性酶和过程的影响，并记录存在的任何抗菌/抗癌活性，以扩大在这一领域的知识。替换金属离子的能力还开放了可以为癌症诊断中使用的正电子发射断层扫描（PET）创建独特的医学成像剂的可能性。该项目的目的是：1。合成钴胺素（Cu，Rh，Zn和Ni）的一系列金属类似物。2。研究金属类似物的生物学特性（例如维生素摄取/转运，酶抑制，抗菌/抗癌剂）.3。工程师的大肠杆菌菌株，能够产生无钴钴胺（氢化脂蛋白）。