Bioproduction of a high-value synthetic ketone ester and its precursors for a UK-based value and supply chain

生物技术在许多类型产品的生产中都很重要，并且在未来将变得越来越重要，原因如下：(1)许多传统制造业依赖于化石碳资源产生的能源和/或化学品，但迫切需要向环境和经济上可持续的循环经济过渡，以减少温室气体排放，限制气候变化和限制环境退化。生物技术可以提供可持续的替代方案。(2)生物技术在生产某些产品方面比传统的非生物方法优越，因为它们在效率、成本和对某些化学反应的控制方面具有重要的优势。(3)生物活性化学物质在医药、营养和农业等领域具有重要意义，这些领域都是积极增长和发展的领域，有望产生许多新产品。生物技术在生产这类化学品方面往往具有优势。(4)向可持续循环经济的转型和上述类型产品的发展为英国、美国和欧盟等先进的高科技经济体开发、利用和出口所需的技术提供了巨大的经济机会。该项目重点关注一种名为酮酯的新产品及其生产中使用的两种关键化学前体，即(R)-3-羟基丁酸酯（R3HB）和(R)-1,3-丁二醇（R13BD）。酮酯是一种“营养品”。营养保健品是一类作为营养补充剂消费的产品，但它提供的额外益处超出了常规食物或营养素，这类产品通常与药物有关，因此称为营养保健品。酮酯的开发和商业化是牛津大学衍生公司TdeltaS的重点。TdeltaS进行的许多研究表明，酮酯作为饮料饮用是安全的，一旦进入人体，就会迅速分解成天然的“酮体”，对人体有益。酮体是一种特殊的能量来源，尤其擅长为大脑和血液提供能量。酮体自然存在于人体内，但通常只有在饥饿或特殊饮食时才会产生，这会导致健康问题。食用酮酯提供了一种快速、安全、方便的方式来获得酮体的益处，研究发现它在提高运动成绩、防御和治疗各种疾病方面都有益处。至关重要的是，酮酯已获得监管部门的批准，并已在美国作为消费者营养保健品进入高价值市场。对酮酯的巨大需求，尤其是来自运动员的需求，已经迅速超过了供应。在英国开发可靠的R3HB和R13BD作为酮酯的化学前体，将提高酮酯的生产规模和商业成功，使市场增长以反映巨大的需求。R3HB和R13BD在其他行业也有许多其他用途，作为化学品，具有成熟的市场。R3HB和R13BD的化学结构意味着它们可以通过生物技术手段非常有效地生产。该项目的工业合作伙伴CHAIN生物技术公司此前已经生产出了生产R3HB和R13BD的工程微生物菌株，但只能与其他产品混合使用，这并不适合当前的目标。该项目的总体目标是运用学术申请人和工业合作伙伴CHAIN Biotechnology的综合专业知识、经验和能力，开发能够生产R3HB和/或R13BD的新微生物菌株，使其足以用于生产这些化学品。该项目还将展示在工程细胞中生产酮酯本身，这可能会在未来导致更简单的酮酯生物制造过程。

Biological technologies are important in the production of many types of products, and will become increasingly important in future, for several reasons:(1) Much conventional manufacturing relies on energy and/or chemicals generated from fossil carbon resources, but there is an urgent need to transition to environmentally and economically sustainable circular economies in order to decrease greenhouse gas emissions, limit climate change and limit environmental degradation. Biological technologies can provide sustainable alternatives.(2) Biological technologies are, or could be, superior to conventional non-biological methods of producing some types of products, because they provide important advantages in the efficiency, costs, and control over some types of chemical reactions.(3) Biologically active chemicals are important in medicine, nutrition and agriculture, all of which are actively growing and developing areas in which many new products can be expected. Biological technologies often have advantages in production of these types of chemicals.(4) The transition to sustainable circular economies and development of the above types of products represent huge economic opportunities for advanced, high-tech economies like the UK, the US and EU to develop, exploit and export the technologies that will be required.This project is focused on a new product called ketone ester and two key chemical precursors used in its production, called (R)-3-hydroxybutyrate (R3HB) and (R)-1,3-butanediol (R13BD). Ketone ester is a 'nutraceutical'. Nutraceuticals are a class of products consumed as nutritional supplements, but which provide additional benefits beyond regular food or nutrients, of the kind more commonly associated with pharmaceuticals, hence the term nutraceutical.Development and commercialisation of ketone ester is the focus of University of Oxford spin-out company TdeltaS. TdeltaS has performed many studies showing that ketone ester is safe to consume as a drink, and once inside the body is quickly broken down into natural 'ketone bodies' with beneficial effects. Ketone bodies are exceptional sources of energy, and are especially good at providing energy to the brain and blood. Ketone bodies are naturally found in the human body, but are only usually made during starvation or during special diets which can cause health problems. Consumption of ketone ester provides a rapid, safe and convenient way to obtain the benefits of ketone bodies, and studies have found benefits in enhancing athletic performance, in defence, and the potential to treat various diseases. Crucially, ketone ester has regulatory approval and has already reached a high-value market as a consumer nutraceutical in the US. Great demand for ketone ester, particularly from athletes, has rapidly outstripped supply.Developing a reliable UK supply of R3HB and R13BD as chemical precursors for ketone ester would improve the scale of production and commercial success of ketone ester, allowing the market to grow to reflect the great demand. R3HB and R13BD also have many other uses as chemicals in other industries, with established markets. The chemical structures of R3HB and R13BD mean they can be very effectively produced by biotechnological means.This project's industrial partner, CHAIN Biotechnology, has previously generated engineered microbial strains which produce R3HB and R13BD, but only in mixtures with other products, which does not suit the current aim.The overall aim of this project is to apply the combined expertise, experience and capacity of the academic applicants and industrial partner CHAIN Biotechnology to develop new strains of microorganisms which produce R3HB and/or R13BD well enough that they could be used to manufacture these chemicals. The project will also demonstrate production of the ketone ester itself in engineered cells, which could lead to a simpler biomanufacturing process for ketone ester in future.