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

BioDiMet的目标是实施大自然的战略，将目标化合物选择性甲基化，作为一个强大的酶平台，准备在早期工业规模上使用。在自然界中，甲基化是由称为SAM依赖的甲基转移酶的酶来执行的，这是完成和提高化合物生物活性的关键步骤。这些反应可以以选择性的方式进行，使用现有的化学合成方法很难实现这一点，因为这些方法主要使用有毒的甲基化试剂，如甲基碘和硫酸二甲酯。酶法具有可持续发展、避免使用有毒试剂和反应选择性好等优点。这与在数十亿英镑的制药、农用化学品和香料/香料行业市场上开发新型生物活性物质的需求密切相关。尽管SAM依赖的甲基转移酶在自然界很重要，但在工业合成中完全没有得到充分利用。这主要是因为需要一种额外的化合物，即辅因子，即S-腺苷甲硫氨酸。这是非常昂贵的购买。为了解决这一问题，可以使用SAM共因供应/回收系统，但尚未提供这些系统。此外，还需要一个强大的甲基转移酶工具箱。近年来，BioDiMet联盟的成员通过建立具有集成的SAM辅助因子供应或回收的智能酶甲基化级联，证明这些限制不再适用。BioDiMet现在是这些酶在工业上工业化的下一步。该项目将生产一个甲基转移酶工具箱，该工具箱对一系列化学结构起作用，并使用SAM辅助因子供应或再循环系统。它们将与其他酶一起用于对重要类别的化合物产生可持续的反应级联。此外，我们还将提高甲基转移酶的稳定性，使其能够用于工业。该项目内放大反应和下游加工方法的开发也将促进平台技术的工业可行性。因此，BioDiMet将提供工具，通过强大的选择性生物催化甲基化来合成新的生物活性物质，并通过化合物文库的甲基化来开发新的活性药物成分。甲基转移酶谱的开发可能使人们能够获得大量以前无法获得的具有理想性质的各种生物活性物质，从而为工业提供新的产品。

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.