17-ERACoBioTech Methyl Transferases for the Functional Diversification of Bioactives: BioDiMet

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BioDiMet aims to implement Nature's strategy to selectively methylate target compounds as a robust enzymatic platform ready for use at an early industrial scale. In Nature methylation is performed by enzymes called SAM-dependent methyl transferases, and this is a key step to accomplish and enhance the bioactivity of compounds. The reactions can occur in a selective manner and this is very difficult to achieve using established chemical synthetic methods where mainly toxic methylation agents such as methyl iodide and dimethyl sulfate are used. Enzymatic approaches have the advantages of sustainability, the avoidance of such toxic reagents, and reaction selectivity. This is of great relevance to the need for the development of novel bioactives in multi-billion pound markets of the pharma, agrochemical and fragrance/flavour industries. Despite the importance in Nature, SAM-dependent methyl transferases are completely underexploited in industrial synthesis. This is mainly because an additional compound, a co-factor, is required known as S-adenosyl methionine (SAM). This is extremely expensive to purchase. To overcome this problem SAM co-factor supply/recycling systems can be used but these have not been available. In addition, a robust methyl transferase enzyme toolbox is needed. In recent years members of the BioDiMet consortium demonstrated that these limitations do not hold true anymore by establishing smart enzymatic methylation cascades with integrated SAM co-factor supply or recycling. BioDiMet is now the next step towards industrialisation of these enzymes in industry. The project will produce a toolbox of methyl transferases that are active towards a range of chemical structures and use SAM co-factor supply or recycling systems. They will be used with other enzymes to produce sustainable reaction cascades to important classes of compounds. In addition we will improve the robustness of the methyl transferases so they can be used by industry. Development of scaled-up reactions and down-stream processing methods within the project will also facilitate the industrial feasibility of the platform technology. BioDiMet will therefore provide tools to synthesize new bioactives through powerful selective biocatalytic methylation and holds significant potential to develop novel active pharmaceutical ingredients via the methylation of compound libraries. Development of a spectrum of methyl transferases potentially allows access to a plethora of previously unobtainable diverse bioactives with desirable properties to deliver new products for industry.