Development of amine-dehydrogenase and lyase biocatalysts for the sustainable manufacturing of unnatural chiral amino acids and amino alcohols

开发胺脱氢酶和裂解酶生物催化剂，用于可持续生产非天然手性氨基酸和氨基醇

• 批准号: 2870226
• 金额: --
• 依托单位: University College London
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2870226
• 关键词: Development; amine; dehydrogenase; lyase; biocatalysts

This project comes as the result of an established collaboration between Dr Castagnolo, UCL and Almac and it aims to develop new biocatalysts, amine dehydrogenase (AD) and lyase (LY) enzymes, for the sustainable industrial production of chiral unnatural amino acids (AAc) and amino alcohols (AAl) as essential building blocks in the manufacturing of drugs and chemicals of industrial relevance.This project is in line with BBSRC's strategic priority in "new strategic approaches to industrial biotechnology".The AAc motif is of crucial importance in biochemistry, being the key building block of peptides and proteins and being involved in almost every biological process. Unnatural analogues of AAc find broad application in industry, as fundamental components of peptide-based pharmaceuticals, antibody drug conjugates and in the synthesis of small molecules, due to their ability to confer to such drugs increased potency, atypical conformations and metabolic resistance. Similarly, chiral AAl's are key motifs in many pharmaceutical ingredients and can be also used as precursors in the production of unnatural AAc. The chemical synthesis of chiral unnatural AAc/AAl is not trivial, it requires harsh reaction conditions and still represents a major challenge for both academia and industry. Given the biological and pharmaceutical importance of these molecules, the UK industry has high interest to identify new strategic research to underpin the development of innovative, green and mores sustainable manufacturing routes to prepare high-value AAc/AAl.In collaboration with Almac, that has world leading experience in the manufacturing of drugs and chemicals through biocatalytic solutions, this project aims to develop new enzymes which can be exploited in the industrial production of unnatural AAc/AAl. The objectives of the project are:1) To develop new biocatalysts (amine dehydrogenases and ammonia/aldehyde lyases) for the the synthesis of unnatural AAc and AAl.2) To exploit the new enzymes in the development of new manufacturing methodologies to produce unnatural AAc and AAl in a sustainable and green manner. 3) To translate these methodologies developed in academia into industrial manufacturing processes4) To offer the PhD student appointed with this project a multidisciplinary training in sustainable chemistry and industrial biotechnology, combining molecular biology, metagenomics, computational bio-engineering and biochemistry with chemical synthesis, automated screening and industrial manufacturing processes.New amine dehydrogenase and lyase enzymes will be developed and engineered taking advantage of the facilities and industrial platforms available at Almac. The AD and ammonia LY enzymes will be used to convert keto- and unsaturated carboxylic acids, in turn obtained from nitrile precursors, into the desired unnatural AAc. Nitrilase enzymes will also be used in the project to produce in situ ammonia as substrate for AD and LY biocatalysts making the process even more sustainable. The aldehyde LY enzymes will be used to produce, new keto-alcohol precursors of AAl through the formation of new carbon-carbon bonds. This project will allow to obtain unnatural AAc and AAl from commercially available and cheap substrates through entirely biocatalytic transformations. The produced AAc/AAl will be made commercially available by Almac as well as the new biocatalysts generated in the project will be added to the Almac biocatalysis toolbox and commercialised.

This project comes as the result of an established collaboration between Dr Castagnolo, UCL and Almac and it aims to develop new biocatalysts, amine dehydrogenase (AD) and lyase (LY) enzymes, for the sustainable industrial production of chiral unnatural amino acids (AAc) and amino alcohols (AAl) as essential building blocks in the manufacturing of drugs and chemicals of industrial relevance.This project is与BBSRC在“新的工业生物技术方法”中的战略优先事项一致。AAC图案在生物化学中至关重要，是肽和蛋白质的关键基础，并且几乎参与了每个生物学过程。 AAC的非自然类似物在行业中发现了广泛的应用，作为基于肽的药物的基本成分，抗体药物结合物和小分子的合成，由于它们能够赋予此类药物的能力会增加耐药性，非典型构象和代谢性。同样，手性AAL是许多药物成分中的关键基序，也可以用作不自然AAC生产的前体。手性不自然AAC/AAL的化学合成并不是微不足道的，它需要严酷的反应条件，并且仍然代表了学术界和行业的主要挑战。鉴于这些分子的生物学和药物重要性，英国行业具有浓厚的兴趣，可以确定新的战略研究以发展创新，绿色和道德的发展，可持续制造途径，以准备与Almac合作的高价值AAC/AAL.IN与Almac合作，该途径在世界上通过生物促进了该项目的生产，从而在世界上领先于该项目，从而可以促进该项目，从而促进该项目，从而促进该项目，从而可以促进新的项目，从而可以促进该项目的新作品。不自然的AAC/AAL。该项目的目的是：1）开发新的生物催化剂（胺脱氢酶和氨/醛裂解酶）以合成非天然AAC和AAL的合成。 3）将学术界开发的这些方法转化为工业制造过程。4）为该项目任命的博士学位学生提供可持续化学和工业生物技术学的多学科培训，将分子生物学，计算生物学，计算生物学和生物化学和生物化学及化学筛选过程结合起来，将其结合在一起将开发和设计利用Almac可用的设施和工业平台。 AD和氨酶酶将用于转化从硝酸前体获得的酮和不饱和羧酸，转化为所需的非天然AAC。硝酸酶也将在该项目中用于生产原位氨，作为AD和LY生物催化剂的底物，使得该过程更加可持续。通过形成新的碳碳键，将使用醛酶来生产AAL的新酮醇前体。该项目将允许通过完全生物催化转化从市售和廉价的底物中获得不自然的AAC和AAL。 ALMAC以及项目中生成的新生物催化剂将在ALMAC生物催化工具箱中添加并商业化。