Rapid Evolution of Enzymes and Synthetic Micro-organisms for the Development of Industrial Biocatalysts

在未来的10-20年里，世界各地的化学工业将经历一次重大变革。随着石油和天然气开始枯竭，社会将需要寻找传统上从这些化石燃料中提取的化学物质的替代来源。由于需要开发既经济又环境可持续的工艺，化学工业将越来越多地转向可再生原料，以制造越来越多的产品。这些产品种类繁多，产量很大，包括化妆品、药品、汽车零部件和燃料。这种从石油为基础的原料向来自生物质的原料的转变将需要发展基于工业（白色）生物技术的工艺，能够有效地将廉价的原料转化为高价值的产品。工业生物技术涉及使用自然界的催化剂，即酶，来生产化学品和相关产品。出现的新机会是聪明地合理设计和构建工程生物催化剂和多酶途径，这些途径能够将简单，低成本的可再生原料（例如纤维素，脂质，废生物质）有效和稳定地转化为每个高价值的最终产品。在某些情况下，这些生物催化转化将由分离的酶进行，由惰性载体支撑。在其他应用中，特别是多酶转化，这些过程将需要在微生物细胞环境中进行——即所谓的“工程细胞工厂”——从而使生产成本最小化，使传统的制造技术失去竞争力。这种能够进行预编程合成转化的细胞的设计和工程是IB面临的一个重大挑战，需要合成化学、合成系统生物学和过程工程等学科的相互作用。在与世界最大的制药公司之一葛兰素史克（GSK）的合作下，曼彻斯特大学的科学家团队将开发一种新的方法，通过在实验室中模仿达尔文的进化过程来设计强大的生物催化剂。这种新的平台技术将使我们能够在几周内优化酶的工业应用，而不是目前需要几个月的时间。我们将通过特别针对六种不同的合成转化来展示这种新技术的力量，这些转化是希望在活性药物成分（api）的制造中使用生物催化的化学家感兴趣的。这些生物催化反应被特别选择，因为它们为传统的合成化学方法提供了非常有竞争力的替代品。这些强大的生物催化剂将以足够高的浓度、通量和产量产生感兴趣的分子，即使在原油价格低的情况下也能确保经济可行性。在项目的不同阶段，我们将把这些生物催化剂转移给GSK， GSK将把它们应用于他们感兴趣的内部分子。我们还将在公开文献中发表研究结果，并通过基于网络的工具提供新方法。

During the next 10-20 years the chemical industry around the world will undergo a major transformation. As both oil and natural gas begin to run out society will need to look for alternative sources of the chemicals that have traditionally been derived from these fossil fuels. Driven by the need to develop processes that are both economically and environmentally sustainable, the chemical industry will increasingly turn to renewable feedstocks for the manufacture of a growing range of products. Such products are diverse and produced in large volume and include cosmetics, pharmaceutical drugs, components of automobiles and also fuels. This switchover from oil-based starting materials to those derived from biomass will necessitate the development of Industrial (White) Biotechnology-based processes that are able to convert inexpensive raw materials efficiently to high-value products. Industrial Biotechnology involves the use of Nature's catalysts, known as enzymes, for the production of chemicals and related products. The new opportunity that emerges is to be smart with the rational design and construction of engineered biocatalysts and multi-enzyme pathways that are capable of the efficient and robust conversion of simple, low-cost renewable feedstocks (e.g. cellulose, lipids, waste biomass) to each high value end product. In some cases these biocatalytic transformations will be carried out by isolated enzymes, supported on an inert carrier. In other applications, especially for multi-enzyme conversions, the processes will need to be carried out within the environment of a microbial cell - the so-called 'engineered cell factory' - thereby minimizing production costs and rendering conventional manufacturing technologies uncompetitive. The design and engineering of such cells, which are capable of pre-programmed synthetic conversions, represents a significant challenge for IB and will require the interaction of the disciplines of synthetic chemistry, synthetic-systems biology and process engineering. In collaboration with GlaxoSmithKline (GSK), one of the world's largest pharmaceutical companies, the team of scientists at the University of Manchester will develop a new approach to engineering robust biocatalysts by essentially mimicking the process of Darwinian evolution in the laboratory. This new platform technology will enable us to optimise enzyme for industrial applications in a matter of weeks rather than the months which it currently takes. We will demonstrate the power of this new technology by specially targeting six different synthetic transformations which are on interest to chemists who wish to use biocatalysis in the manufacture of active pharmaceutical ingredients (APIs). These biocatalytic reactions have been specifically chosen because they offer very competitive alternatives to conventional synthetic chemistry methods. These robust biocatalysts will produce the molecules of interest at sufficiently high concentrations, fluxes and yields to ensure economic viability even when crude oil prices are low. At various stages during the project we shall transfer these biocatalysts to GSK who will then apply them to their in-house molecules of interest. We shall also publish the results of the research in the open literature and make the new methods available by web-based tools.