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Unlocking the potential of engineered C-C bond forming enzymes for biocatalysis

释放工程化 C-C 键形成酶的生物催化潜力

基本信息

批准号：
BB/T001968/1
负责人：
Paul Race
金额：
$ 98.13万
依托单位：
University of Bristol
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2019
资助国家：
英国
起止时间：
2019 至无数据
项目状态：
未结题

来源：
https://gtr.ukri.org/projects?ref=BB%2FT001968%2F1
关键词：
Unlocking potential engineered bond forming

项目摘要

The future success of the global pharmaceutical and chemical industries is dependent on the successful development of efficient, selective and sustainable ways of making new organic molecules with useful properties. Historically, such methods have centered on the use of synthetic organic chemistry to fuse and tailor simple chemical building blocks into a vast array of complex molecular architectures, which may in-turn be used as the basis for amongst other things new drugs, crop protection agents, or materials. Despite the undoubted success of synthetic chemistry, problems exist, including the over-reliance on certain types of reactions that have led to an excessive representation of molecules with predominantly flat, 2D architectures, which are of limited value as drugs. In contrast to chemical catalysts, biological catalysts, termed enzymes, are able to perform challenging chemical reactions that can rapidly build complex 3D chemical structures with multiple bonds under precise stereochemical control. In addition, enzymes can perform such reactions under ambient conditions and without any requirement for environmentally damaging reagents. For these reasons there is significant interest in developing biocatalytic routes to current and future pharmaceuticals and similarly important molecules. A carbon-carbon bond forming reaction known as the Diels-Alder reaction is an effective means of building complex 3D molecules in a single step. However, a limitation of this reaction is that to achieve high yields, stereoselectivity and regioselectivity, the electronic properties of the reactants need to be complementary and often harsh reaction conditions are required. This research project builds on our exciting recent discovery of a naturally evolved co-factor independent enzyme that catalyzes the Diels-Alder reaction at room temperature and on substrates which cannot be transformed using conventional synthetic organic chemistry. This discovery opens up the possibility of using this enzyme to generate a whole new series of complex molecules that could form the basis of new drugs or similarly important chemical compounds. During this project we will establish the practical and theoretical limits of the reactions that this and other related Diels-Alderases can catalyze, we will also rationally re-engineer these enzyme to purposefully change their function to allow access to an even greater variety of products. We will partner these engineered biocatalysts with auxiliary enzymes which catalyze further ring forming reactions to develop routes to industrially useful molecules. This project is a strategically important partnership between the University of Bristol and the pharmaceutical company AstraZeneca, and we will work together to develop natural and engineered enzymes and deploy them to generate a vast array of new 3D molecules that can be used as the basis for new drugs to treat a diverse array of human diseases.

全球制药和化学工业未来的成功取决于成功开发出高效、选择性和可持续的方法来制造具有有用性质的新有机分子。历史上，这种方法的中心是使用合成有机化学将简单的化学构件融合并定制成大量复杂的分子结构，这些分子结构反过来又可以用作新药、作物保护剂或材料等的基础。尽管合成化学无疑是成功的，但问题仍然存在，包括过度依赖某些类型的反应，导致过度代表以平面、2D结构为主的分子，这些分子作为药物的价值有限。与化学催化剂不同，生物催化剂，称为酶，能够执行具有挑战性的化学反应，可以在精确的立体化学控制下快速建立具有多个键的复杂3D化学结构。此外，酶可以在环境条件下执行这种反应，而不需要任何破坏环境的试剂。出于这些原因，人们对开发通往当前和未来药物以及类似重要分子的生物催化路线非常感兴趣。一种称为Diels-Alder反应的碳-碳键形成反应是一种在一步内构建复杂3D分子的有效方法。然而，该反应的局限性在于，要获得高产率、立体选择性和区域选择性，反应物的电子性质需要互补，而且通常需要苛刻的反应条件。这一研究项目建立在我们最近令人兴奋的发现的基础上，即一种自然进化的辅因子独立酶，它在室温下催化Diels-Alder反应，并在使用传统合成有机化学无法转化的底物上催化。这一发现开启了使用这种酶产生一系列全新的复杂分子的可能性，这些分子可能构成新药或类似重要化合物的基础。在这个项目中，我们将建立该酶和其他相关Diels-Alderase可以催化的反应的实际和理论限制，我们还将合理地重新设计这些酶，有目的地改变它们的功能，以允许获得更多种类的产品。我们将把这些工程生物催化剂与辅助酶配对，这些辅助酶催化进一步的环形成反应，以开发出工业上有用的分子的路线。该项目是布里斯托尔大学和阿斯利康制药公司之间具有重要战略意义的合作伙伴关系，我们将合作开发天然和工程酶，并部署它们来生成大量新的3D分子，这些分子可以用作治疗各种人类疾病的新药的基础。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Unlocking the Therapeutic Potential of Antimicrobial Natural Products with Synthetic Biology

利用合成生物学释放抗菌天然产物的治疗潜力

DOI：
发表时间：
2020
期刊：
International Biopharmaceutical Industry
影响因子：
0
作者：
Rooms LD
通讯作者：
Rooms LD

The Role of Cytochrome P450 AbyV in the Final Stages of Abyssomicin C Biosynthesis

细胞色素 P450 AbyV 在 Abyssomicin C 生物合成最后阶段的作用

DOI：
10.1002/ange.202213053
发表时间：
2022
期刊：
Angewandte Chemie
影响因子：
0
作者：
Devine A
通讯作者：
Devine A

A New Micromonospora Strain with Antibiotic Activity Isolated from the Microbiome of a Mid-Atlantic Deep-Sea Sponge.

DOI：
10.3390/md19020105
发表时间：
2021-02-11
期刊：
Marine drugs
影响因子：
5.4
作者：
Back CR;Stennett HL;Williams SE;Wang L;Ojeda Gomez J;Abdulle OM;Duffy T;Neal C;Mantell J;Jepson MA;Hendry KR;Powell D;Stach JEM;Essex-Lopresti AE;Willis CL;Curnow P;Race PR
通讯作者：
Race PR

SAXS reveals highly flexible interdomain linkers of tandem acyl carrier protein-thioesterase domains from a fungal nonreducing polyketide synthase