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

17-ERACoBioTech 甲基转移酶用于生物活性物质的功能多样化：BioDiMet

• 批准号: BB/R021643/1
• 负责人: Helen Hailes
• 金额: $ 62.18万
• 依托单位: University College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2018
• 资助国家: 英国
• 起止时间: 2018 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FR021643%2F1
• 关键词: 17; ERACoBioTech; Methyl; Transferases; Functional

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.

BioDiMet旨在实施Nature的策略，选择性地甲基化目标化合物，作为一个强大的酶平台，可用于早期工业规模。在自然界中，甲基化是由称为SAM依赖性甲基转移酶的酶进行的，这是实现和增强化合物生物活性的关键步骤。反应可以以选择性的方式发生，这是非常难以使用已建立的化学合成方法来实现的，其中主要使用有毒的甲基化试剂，如甲基碘和硫酸二甲酯。酶促方法具有可持续性、避免此类毒性试剂和反应选择性的优点。这与在制药、农业化学和香料/调味品行业的数十亿磅市场中开发新型生物活性物质的需求非常相关。尽管在自然界中很重要，但SAM依赖性甲基转移酶在工业合成中完全未得到充分利用。这主要是因为需要一种额外的化合物，一种辅因子，称为S-腺苷甲硫氨酸（SAM）。这是非常昂贵的购买。为了克服这个问题，可以使用SAM辅助因子供应/再循环系统，但这些系统还没有可用。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中工业化的下一步。该项目将产生一个甲基转移酶工具箱，这些甲基转移酶对一系列化学结构具有活性，并使用SAM辅助因子供应或回收系统。它们将与其他酶一起使用，产生可持续的反应级联，以产生重要类别的化合物。此外，我们将提高甲基转移酶的稳健性，以便它们可以被工业使用。在该项目内开发扩大规模的反应和下游加工方法也将促进该平台技术的工业可行性。因此，BioDiMet将通过强大的选择性生物催化甲基化提供合成新生物活性物质的工具，并具有通过化合物库的甲基化开发新型活性药物成分的巨大潜力。甲基转移酶谱的开发潜在地允许获得过多的先前无法获得的具有期望性质的多样生物活性物质，以向工业提供新产品。

项目成果

Expanding the Substrate Scope of N - and O -Methyltransferases from Plants for Chemoselective Alkylation

扩大植物中 N - 和 O - 甲基转移酶的底物范围以进行化学选择性烷基化

• DOI: 10.1101/2023.07.21.549995
• 发表时间: 2023
• 作者: Jockmann E

Direct Conversion of Hydrazones to Amines using Transaminases.

• DOI: 10.1002/cctc.202101008
• 发表时间: 2021-11-08
• 期刊: CHEMCATCHEM
• 影响因子: 4.5
• 作者: Carter, Eve M.;Subrizi, Fabiana;Ward, John M.;Sheppard, Tom D.;Hailes, Helen C.
• 通讯作者: Hailes, Helen C.

Characterisation of a hyperthermophilic transketolase from Thermotoga maritima DSM3109 as a biocatalyst for 7-keto-octuronic acid synthesis.

• DOI: 10.1039/d1ob01237a
• 发表时间: 2021-07-28
• 期刊: Organic & biomolecular chemistry
• 影响因子: 3.2
• 作者: Cárdenas-Fernández M;Subrizi F;Dobrijevic D;Hailes HC;Ward JM
• 通讯作者: Ward JM

A transaminase-mediated aldol reaction and applications in cascades to styryl pyridines

• DOI: 10.1039/d3cy01370g
• 发表时间: 2024-03-01
• 期刊: CATALYSIS SCIENCE & TECHNOLOGY
• 影响因子: 5
• 作者: Wang，Yu;Li，Yiwen;Hailes，Helen C.
• 通讯作者: Hailes，Helen C.

A bicyclic S-adenosylmethionine regeneration system applicable with different nucleosides or nucleotides as cofactor building blocks.

• DOI: 10.1039/d1cb00033k
• 发表时间: 2021-03-22
• 期刊: RSC chemical biology
• 影响因子: 4.1
• 作者: Popadić D;Mhaindarkar D;Dang Thai MHN;Hailes HC;Mordhorst S;Andexer JN
• 通讯作者: Andexer JN