Molecular X-Factor & SynBioFilms

点击翻译按钮获取中文摘要

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