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

通过设计支架和隔间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一个主要愿望。在这里，我们通过重新设计和合理设计天然支架和细胞器来解决这个问题。事实上，众所周知，自然界使用隔间来有效地浓缩和/或分离特定细胞器中的特定蛋白质。通过这种方式，酶等活性成分可以更好地接触到它们的底物，但也防止了有毒物质在细胞内扩散。在BBSRC的关键战略领域之一，合成生物学的一个主要目标是设计和/或改进现有的自然系统，并利用这些系统生产具有商业价值的重要化学品和生物治疗药物。由于细胞内的大多数隔室都受到脂膜的限制，因此人们对非脂膜/蛋白质壳限制的隔室的兴趣和潜力越来越大。在这项建议中，我们将利用细菌微隔室(BMC)和自组装肽笼(SAGE)作为这种非脂结合隔室的指数。与脂质结合的细胞器相比，蛋白质隔间的一个可能的优势是运输进出隔间。我们的总体目标是(让细胞)建立新陈代谢微型工厂，能够在不使细胞中毒的情况下生产有用的或有价值的分子。通过这种方式，我们可能会开发出生产精细和平台化学品以及生物疗法的新方法。肯特大学、布里斯托尔大学和玛丽女王大学一直站在研究骨髓基质细胞和圣人的前沿，并揭示了大量的基本原理。因此，我们处于极佳的地位，可以将这些研究提高到一个新的水平：将新的代谢过程引入隔间，在细胞内表达这些系统，并最终将它们用于“大规模”生产。为了实现这一雄心勃勃的目标，我们组建了一支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。只有通过这种集成的方法，才有可能设计出所需的功能细菌工厂。此外，通过在三个站点之间交换概念、想法和技术，我们将能够独立完成比每个小组更多的工作。重要的是要强调化学/制药部门对这项研究的浓厚兴趣，他们将能够指导我们找到有价值的目标，但也可能是进一步开发和转化该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和生物疗法做出贡献，并与领先的公司一起将其迅速纳入制造。

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.