Synthetic Biology Pathways to Isoquinoline Alkaloids

异喹啉生物碱的合成生物学途径

• 批准号: BB/G014426/1
• 负责人: John Ward
• 金额: $ 90.88万
• 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: 2009
• 资助国家: 英国
• 起止时间: 2009 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FG014426%2F1
• 关键词: Synthetic; Biology; Pathways; Isoquinoline; Alkaloids

For thousands of years mankind has been using plants and medicinal compounds from plants for treating pain, diseases, infections and also for recreational purposes. Many of these plant derived compounds have also found their way into modern drug use for example morphine and codeine for pain relief, atropine to increase heart rate and for irritable bowel syndrome, vinblastine to treat cancers and quinine for malaria. There are over 14,000 alkaloid chemical structures known and these represent a wealth of potential biological activity. However many of these alkaloids occur in small amounts or in plants that are rare or only grow in parts of the world that are difficult to access. The pathways that plants use to synthesise alkaloids are often long with many biosynthetic steps. There are some key intermediate compounds that are common to many plant alkaloid pathways and the complexity of alkaloid structures comes from the different later steps in the pathways that different plants have. It would be of great benefit to be able to make some of these key intermediate alkaloid compounds in a more controlled way and to be able to modify these alkaloid structures using enzymes or chemistry. In this way novel biologically active drugs could be found. The pathways for the synthesis of several alkaloids have begun to be determined but many of the steps for some of the more complex alkaloids are still unknown. In the last few years researchers have begun to isolate the enzymes (and their genes) for some of the key steps in the synthesis of some alkaloids. Some of these enzymes carry out very important steps such as the joining together of rather simple compounds derived from simple amino acids. We intend to use the techniques of whole gene synthesis, synthetic biology and pathway design to make some of these key alkaloid synthesising enzymes and put them into a laboratory bacterium. In this way we can combine different plant based and bacterial enzymes and build synthetic pathways for the creation of new chemical compounds that could be screened for useful medicinal activities. By having the pathways in bacteria we would be able to generate them in a reproducible way using a renewable resource and not be dependant on the growth of difficult or rare plants. In addition, extensive chemical transformations using methods with high environmental impact would not be required which are currently used to synthesise such isoquinolines.

几千年来，人类一直在使用植物和来自植物的药用化合物来治疗疼痛、疾病、感染以及娱乐目的。这些植物衍生化合物中的许多也已被发现用于现代药物用途，例如用于缓解疼痛的吗啡和可待因，用于增加心率和治疗肠易激综合征的阿托品，用于治疗癌症的长春碱和用于疟疾的奎宁。已知有超过14，000种生物碱化学结构，这些代表了丰富的潜在生物活性。然而，这些生物碱中的许多以少量或在罕见或仅生长在世界上难以获得的部分地区的植物中出现。植物用于合成生物碱的途径通常很长，具有许多生物合成步骤。有一些关键的中间体化合物是许多植物生物碱途径所共有的，生物碱结构的复杂性来自不同植物所具有的途径中的不同后期步骤。如果能够以更可控的方式制造这些关键中间体生物碱化合物中的一些，并且能够使用酶或化学方法修饰这些生物碱结构，这将是非常有益的。一些生物碱的合成途径已经开始被确定，但一些更复杂的生物碱的许多步骤仍然是未知的。在过去的几年里，研究人员已经开始分离合成某些生物碱的关键步骤中的酶（及其基因）。这些酶中的一些进行非常重要的步骤，例如将来自简单氨基酸的相当简单的化合物连接在一起。我们打算利用全基因合成、合成生物学和途径设计等技术来合成这些关键的生物碱合成酶，并将它们放入实验室细菌中。通过这种方式，我们可以联合收割机结合不同的植物酶和细菌酶，并建立合成途径，以产生新的化合物，这些化合物可以被筛选用于有用的药物活性。通过细菌中的途径，我们将能够使用可再生资源以可再生的方式产生它们，而不依赖于困难或稀有植物的生长。此外，不需要使用目前用于合成此类异喹啉的具有高环境影响的方法进行广泛的化学转化。

项目成果

One-pot triangular chemoenzymatic cascades for the syntheses of chiral alkaloids from dopamine

• DOI: 10.1039/c4gc02325k
• 发表时间: 2015-01-01
• 期刊: GREEN CHEMISTRY
• 影响因子: 9.8
• 作者: Lichman, B. R.;Lamming, E. D.;Ward, J. M.
• 通讯作者: Ward, J. M.

The Catalytic Potential of Coptis japonica NCS2 Revealed - Development and Utilisation of a Fluorescamine-Based Assay

• DOI: 10.1002/adsc.201200641
• 发表时间: 2012-11-01
• 期刊: ADVANCED SYNTHESIS & CATALYSIS
• 影响因子: 5.4
• 作者: Pesnot, Thomas;Gershater, Markus C.;Hailes, Helen C.
• 通讯作者: Hailes, Helen C.

Library of Norcoclaurine Synthases and Their Immobilization for Biocatalytic Transformations.

去甲乌云碱合成酶文库及其用于生物催化转化的固定化。

• DOI: 10.1002/biot.201700542
• 发表时间: 2018
• 期刊: Biotechnology journal
• 影响因子: 4.7
• 作者: Lechner H

One-Pot Phosphate-Mediated Synthesis of Novel 1,3,5-Trisubstituted Pyridinium Salts: A New Family of S. aureus Inhibitors.

• DOI: 10.3390/molecules22040626
• 发表时间: 2017-04-12
• 期刊: Molecules (Basel, Switzerland)
• 作者: Pesnot T;Gershater MC;Edwards M;Ward JM;Hailes HC
• 通讯作者: Hailes HC

'Dopamine-first' mechanism enables the rational engineering of the norcoclaurine synthase aldehyde activity profile.

• DOI: 10.1111/febs.13208
• 发表时间: 2015-03
• 期刊: The FEBS journal
• 作者: Lichman BR;Gershater MC;Lamming ED;Pesnot T;Sula A;Keep NH;Hailes HC;Ward JM
• 通讯作者: Ward JM