Development of supramolecular assemblies for enhancing cellular productivity and the synthesis of fine chemicals and biotherapeutics.

通过支架和隔室的工程改造来重新连接和重组细胞内部代谢机制的能力代表了合成生物学的主要愿望。在这里，我们解决这个问题，通过从头和天然支架和细胞器的设计和合理的工程。事实上，众所周知，自然界使用隔室来有效地浓缩和/或分离特定细胞器中的特定蛋白质。通过这种方式，活性成分（如酶）可以更好地接近其底物，但也可以防止有毒物质在整个细胞中扩散。在BBSRC的关键战略领域之一，合成生物学，一个主要目标是设计新的和/或改进现有的天然系统，并利用这些用于生产商业上重要的化学品和生物治疗剂。而大多数细胞内的隔室是由脂质膜限制的，有越来越多的兴趣和潜力，在隔室限制的非脂质/蛋白质外壳。在这个提议中，我们将利用细菌微生物区（BMC）和自组装肽caGE（SAGE）作为这种非脂质结合区室的指数。与脂质结合的细胞器相比，蛋白质隔室的可能优点之一是进出隔室的运输。我们的总体目标是（让细胞）建立代谢微型工厂，能够在不毒害细胞的情况下产生有用和/或有价值的分子。通过这种方式，我们可以开发新的方法来生产精细和平台化学品以及生物治疗剂。肯特大学、布里斯托大学和玛丽女王大学一直处于研究BMC和SAGE的前沿，并解开了大量的基本原理。因此，我们有能力将这些研究提升到一个新的水平：将新的代谢过程引入细胞间，在细胞内表达这些系统，并最终将其用于“大规模”生产。为了实现这一雄心勃勃的目标，我们组建了一个高度跨学科的研究团队，涵盖细胞生物学，化学，生物信息学和工程学等不同领域。只有通过这种综合方法，才有可能设计出所需的功能性细菌工厂。此外，通过3个站点之间的概念、想法和技术交流，我们将能够实现比每个组独立更多的目标。重要的是要强调化学/制药部门对这项研究的重大兴趣，他们将能够指导我们实现有价值的目标，但也可能是进一步发展和转化本项目具体成果的途径。通过本申请中描述的研究，我们相信我们将能够为开发新的可持续方法来产生化学品做出贡献，生物治疗和他们的快速纳入制造业与领先的公司。

The ability to rewire and reorganise the internal metabolic machinery of the cell through the engineering of scaffolds and compartments represents a major aspiration of synthetic biology. Here we address issues to this problem through the design and rational engineering of de novo and natural scaffolds and organelles. Indeed, it is well known that nature uses compartments to efficiently concentrate and/or segregate specific proteins in specific organelles. In this way, active components such as enzymes have better access to their substrates but also toxic substances are prevented from diffusing throughout the cell. In one of the key strategic areas of BBSRC, Synthetic Biology, a major aim is to design from new and / or improve on such existing natural systems and to exploit these for the production of commercially important chemicals and biotherapeutics.Whereas most compartments inside cells are limited by a lipid membrane, there is increasing interest and potential in compartments limited by a non-lipid / proteinaceous shell. In this proposal we will exploit the use of Bacterial MicroCompartments (BMCs) and Self-Assembling peptide caGEs (SAGEs) as exponents of such non-lipid bounded compartments. One of the possible advantages of proteinaceous compartments over lipid-bounded organelles is transport in and out of the compartment. Our overall aim is to (let the cells) build metabolic micro-factories that will be able to produce useful and or valuable molecules without intoxicating the cells. In this way we may develop new ways to produce fine and platform chemicals as well as biotherapeutics.The Universities of Kent, Bristol and Queen Mary have been at the forefront of studying both BMCs and SAGEs and have unravelled a large number of the underlying principles. We are therefore in an excellent position to take these studies to the next level; introducing new metabolic processes into compartments, expressing such systems inside cells, and ultimately use them for "large scale" production.In order to achieve this ambitious goal we have assembled a highly interdisciplinary team of researchers covering such diverse areas as Cell Biology, Chemistry, Bioinformatics, and Engineering. Only via such an integrated approach will it be possible to design the desired functioning bacterial factories. Also, through the exchange of concepts, ideas, and technologies between the 3 sites we will be able to achieve substantially more than each group independently. It is important to highlight the significant interest in this research from the chemical/pharmaceutical sector, who will be able to guide us to valuable targets but may also be a route to further development and translation of specific outcomes of this project.Through the research described in this application we are confident that we will be able to contribute to the development of new sustainable approaches to the generation of chemicals and biotherapeutics and for their rapid incorporation into manufacturing with leading companies.