X-Genix: Translating Halogenases for Sustainable Synthesis

X-Genix：转化卤化酶以实现可持续合成

• 批准号: EP/X030008/1
• 负责人: Rebecca Goss
• 金额: $ 16.47万
• 依托单位: University of St Andrews
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=EP%2FX030008%2F1
• 关键词: Genix; Translating; Halogenases; Sustainable; Synthesis

1a.i. Brief description of the idea to be taken to proof of concept:The manufacture of over 90% of pharmaceuticals includes a halogenation step, addition of a halogen to a carbon, forming a so-called C-X bond. Analysis of 200 top-selling drugs indicated that > 25% of pharmaceuticals contain this halogen (X-factor) in the final product, including drugs for treatment for conditions such as cancer, diabetes, high cholesterol, stomach ulcers, anaemia, asthma, epilepsy, and others. A further 67% use C-X formation in their manufacture (see Fig. 2).The problem: Whilst the ability to selectively make C-X bonds is essential, current chemical halogenation methods to achieve this are inefficient, expensive and require toxic chemicals. They are often accompanied by poor selectivity, which results in non-selective halogenation and undesired by-products, creating difficulties in the downstream purification process, environmentally detrimental waste and loss of precious material with cost implications (Fig.1). Existing methods for halogenating aromatic substrates generally employ highly reactive reagents, which often generate products in which either only the most nucleophilic position is halogenated or mixtures of products are produced.In addition, generation of halogenating reagents is an energy intensive process; for example, energy used for producing chlorine gas currently required for pharmaceutical manufacture alone accounts for >400,000 metric tons of CO2-emission (equating to CO2-emission of over 87000 cars per annum). Enzymes suitable for industrial halogenation had not been available prior to our patented approach to discovery of novel halogenases with broad substrate scope.Figure 1: Major limitations of current chemical halogenations - toxic reagents, non-selective chemistries, adverse safety and environmental impact.The Opportunity and Breakthrough Innovation Potential: Our X-Genix project provides enzymatic halogenation technology and uses natural tools (bespoke enzymes and salt) to selectively install C-X bonds without waste and whilst reducing costs (Fig. 3). Our USP is the patented approach to finding flavin dependent halogenases (FDHs), a patented toolbox of halogenases and our knowhow in producing, engineering and using these sustainable enzymes for greener, cheaper and safer halogenation processes. Why now? There is a critical push in industry toward displacing chemically catalysed reactions with enzymatic reactions, the ambition being that by 2050, 30% of all industrial reactions should be enzyme driven. Notably, halogenation, one of the most important transformations remains missing from the industrial biocatalysis portfolio. This proposal addresses this deficit.

1我。概念验证的想法简要说明：90%以上的药品的制造包括卤化步骤，将卤素添加到碳上，形成所谓的C-X键。对200种畅销药物的分析表明，大约25%的药物在最终产品中含有这种卤素（x因子），包括治疗癌症、糖尿病、高胆固醇、胃溃疡、贫血、哮喘、癫痫等疾病的药物。另外67%的公司在生产中使用C-X地层（见图2）。问题：虽然选择性地制造C-X键的能力是必不可少的，但目前实现这一目标的化学卤化方法效率低下，价格昂贵，而且需要有毒的化学物质。它们通常伴随着较差的选择性，导致非选择性卤化和不希望的副产品，给下游净化过程带来困难，对环境有害的废物和宝贵材料的损失，并带来成本影响（图1）。现有的芳香族底物卤化方法通常采用高活性试剂，其产物要么只卤化最亲核的位置，要么产生混合物。此外，卤化试剂的生成是一个能源密集型的过程；例如，目前仅生产制药所需的氯气所使用的能源就占了40万吨二氧化碳的排放量（相当于每年87000多辆汽车的二氧化碳排放量）。在我们的专利方法发现具有广泛底物范围的新型卤化酶之前，没有适用于工业卤化的酶。图1：当前化学卤化的主要限制-有毒试剂，非选择性化学品，不利的安全和环境影响。机遇和突破性创新潜力：我们的X-Genix项目提供酶卤化技术，并使用天然工具（定制酶和盐）选择性地安装C-X键，不浪费，同时降低成本（图3）。我们的USP是寻找黄素依赖性卤化酶（FDHs）的专利方法，是卤化酶的专利工具箱，以及我们在生产、设计和使用这些可持续酶的专业知识，以实现更环保、更便宜和更安全的卤化过程。为什么是现在?工业上正大力推动用酶促反应取代化学催化反应，目标是到2050年，30%的工业反应都是酶促反应。值得注意的是，卤化，最重要的转变之一，仍然缺少工业生物催化组合。这项提案解决了这一赤字。