Molecular X-Factor & SynBioFilms

该应用建立在我们研究的两个互补方面：-我们之前已经证明了使用SynBioFilms进行酶稳定，提供具有大表面积的长寿命，可动员的催化剂-我们已经证明了发现和利用序列基序来挖掘具有广泛底物特异性的卤化酶。在分子中引入卤素可以用来调节活性、生物利用度和代谢稳定性，因此在农业化学和医学中是一种重要的策略。超过20%的小分子药物和超过80%的上市农用化学品是卤化的。此外，卤化反应是分子构建的重要反应之一。在制药工业中，交叉偶联反应被广泛应用（仅次于酰胺键形成反应）。交叉偶联反应需要卤化中间体。传统的卤化芳香族底物的化学方法通常使用高活性试剂，产生有害废物。由于传统试剂缺乏能够调节产物选择性的成分，它们通常产生的产物要么只有最亲核的位置被卤化，要么是产物的混合物。相反，生物合成（酶）卤化反应温和，选择性高，利用简单的盐如NaCl， NH4Br或NaI作为卤化源，氧作为氧化剂。人们越来越倾向于采用更环保、更有选择性的技术。全球目标是，到2050年，至少30%的工业化学过程将通过酶法进行。卤化酶在工业催化工具箱中明显缺失。尽管全球已经投入了大量的研究来了解黄素依赖的卤化色氨酸，并设计这些卤化物具有稍宽的底物特异性，但很少有研究超越这些简单的色氨酸，吡咯和酚卤化酶。引人注目的是，迄今为止已经发现了5000多种卤化天然产物。它们具有明显不同的结构，因此我们有理由相信具有非常不同底物特异性的卤化酶一定存在。我们开创了在计算机上发现独特卤化酶的方法。通过这些研究，我们首次确定了一个序列基序，该序列基序可以单独用于从序列数据集中挖掘确定为卤化酶的酶。利用这种方法已经发现了具有广泛底物特异性的野生型卤化酶。在这个转化项目中，我们将与制药行业、催化行业的专家和一家具有市场范围专业知识的公司合作，并得到圣安德鲁斯大学的大力支持，该大学正在开发伊甸园校园创新中心，并得到2600万英镑的城市交易资金的支持，我们将：-探索市场机会，建立与现有合作伙伴的关系，同时积极识别和建立与新合作伙伴和潜在客户的关系-开展概念验证研究，为我们的合作伙伴公司AZ寻找定制的卤化酶解决方案-使用我们设计的SynBioFilm平台进行这些生物转化的稳定和升级-与圣安德鲁斯大学，Guy Carter（化学技术退休负责人），惠氏（Wyeth）和Drochaid（一家总部位于圣安德鲁斯的全球催化公司）将分拆一家卤化酶解决方案公司，该公司将设在伊甸园校园创新中心——探索下一步的融资措施，包括许可协议、合作协议、投资和苏格兰企业HGSP计划

This application builds upon two complementary aspects of our research:-We have previously demonstrated the use of SynBioFilms for enzyme stabilisation, affording long lived, mobilised catalysts with a large surface area -We have demonstrated the discovery and utilisation of a sequence motif for the mining of halogenases with broad substrate specificity.The introduction of a halogen into a molecule can be used to modulate activity, bioavailability and metabolic stability, and as such represents an important strategy in agrochemistry and medicine. Over 20% of small molecule drugs and more than 80% of marketed agrochemicals are halogenated. Furthermore, halogenation is one of the most important reactions for molecule building. In the pharmaceutical industry cross-coupling reactions are widely used (being second only to amide bond forming reactions). Halogenated intermediates are required for cross-coupling reactions. Traditional chemical methodologies of halogenating aromatic substrates generally employ highly reactive reagents and generate harmful waste. As traditional reagents lack components that enable the tuning of product selectivity, they oftentimes generate products in which either only the most nucleophilic position is halogenated or mixtures of products are produced. Conversely, biosynthetic (enzymatic) halogenation is mild, highly selective and utilises simple salts such as NaCl, NH4Br or NaI as the source of halide while oxygen serves as the oxidant. There is an increasing drive to employ greener, and more selective technologies. A global aim is that by 2050 at least 30% of industrial chemical processes will be carried out enzymatically. Halogenase enzymes are notably absent from the industrial catalytic toolbox.Though considerable research has been invested globally into understanding flavin dependent halogenates that halogenate tryptophan, and engineering these halogenates to have slightly broader substrate specificity, there are few studies beyond these simple tryptophan, pyrrole and phenol halogenases.Strikingly, over 5000 halogenated natural products have been found to date. These have notably diverse structures, we therefore had reason to believe halogenases with very different substrate specificities must exist.We have pioneered methodology for the in silico discovery of unique halogenases. Through these studies we have identified for the first time a sequence motif that may be used by itself to mine for enzymes which are definitively halogenases, from sequence data sets. Using this approach Wild Type Halogenases with broad substrate specificity have been found.In this translational project, partnering with experts from the pharmaceutical industry, catalysis industry and a company with expertise in market scoping, and strongly supported by the University of St Andrews who are developing Eden Campus Innovation Hub, underpinned by 26M of City Deal funding we will: - explore the market opportunity, and build upon our relationship with existing partners, whilst proactively identifying and building relationships with new partners and potential customers - carry out proof of concept studies finding bespoke halogenase solutions for our partner company AZ- carry out stabilisation and upscaling of these biotransformations using our engineered SynBioFilm platform- work closely with University of St Andrews, Guy Carter (retired head of Chemical Technologies, Wyeth) and Drochaid (a global catalysis company based in St Andrews) toward spinning out a halogenase solutions company, to be based at the Eden campus Innovation Hub- explore next steps of financing, including licensing deals, partnership deals, investment and the Scottish Enterprise HGSP scheme