Synthetic biology approaches to bio-orthogonal chemistry

生物正交化学的合成生物学方法

• 批准号: 1710588
• 负责人: Michelle Chang
• 金额: $ 48万
• 依托单位: University of California-Berkeley
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2020-07-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1710588&HistoricalAwards=false
• 关键词: Synthetic; biology; approaches; bio; orthogonal

Living systems utilize chemistry to interact with the world around them and have evolved many unusual chemical behaviors in different environments. This research seeks to explore and discover new biosynthetic pathways to the make rare but useful functional groups, such as the alkyne. To date, only one mechanism of alkyne formation has been identified. In contrast, soil microbes produce a novel family of terminal alkyne amino acids but the pathway is unknown. Identifying and characterizing the pathway for the biosynthesis may provide new knowledge about how formation of chemical structures such as alkene and alkynes occurs in enzyme active sites. With this award, the Chemistry of Life Processes Program in the Chemistry Division is funding Dr. Michelle Chang to examine the pathway for the biosynthesis of beta-es. Given the unusual transformations involved in this pathway, the enzymes responsible for these eactions are studied in detail to clearly define their mechanisms of action. Understanding their reactivity may allow for applications including tagging of target proteins for imaging in cells and modification of enzymes to make new catalysts. Given the broad range of scientific methodology required for this work, students train in broad interdisciplinary areas at the interface of chemistry and biology with the goal of applying their knowledge to new and complex problems in the study of life processes. Outreach activities at the undergraduatelevel are prioritized to recruit a more diverse student body at the graduate studies level.This research project is undertaken to elucidate the biosynthetic genes involved in the production of beta-ethynylserine in Streptomyces cattleya using a combination of bioinformatic, genetic, and biochemical approaches. Given the unusual nature of the functional group, the mechanism of the enzymes involved in formation of the alkyne are studied in order to elucidate their function and selectivity as well as their potential for identification of new families of enzymes that may find utility in synthetic applications. Upon validiation of the genes for beta-ethynylserine synthesis, this pathway is also tested in vivo for its ability to be transplanted into different host organisms. The research also seeks future applications that introduce the terminal alkyne into protein-based targets. Given the broad range of scientific methodology required for this work, students train in broad interdisciplinary areas at the interface of chemistry and biology, such as bioinformatics, enzymology, microbial genetics, analytical chemistry, and bioengineering with the goal of preparing students to apply their knowledge to new and complex problems in the study of life processes.

生命系统利用化学与周围的世界相互作用，并在不同的环境中进化出许多不寻常的化学行为。本研究旨在探索和发现新的生物合成途径，以制造稀有但有用的官能团，如炔。迄今为止，只确定了一种炔的形成机制。相比之下，土壤微生物产生了一个新的氨基末端氨基酸家族，但其途径尚不清楚。识别和表征生物合成途径可以提供新的知识，如何形成的化学结构，如烯烃和炔烃发生在酶的活性位点。凭借这一奖项，化学部门的生命过程化学项目资助米歇尔·张博士研究β -es的生物合成途径。鉴于这一途径中涉及的不寻常的转化，我们详细研究了负责这些反应的酶，以清楚地定义它们的作用机制。了解它们的反应性可以应用于靶蛋白的标记，用于细胞成像和酶的修饰，以制造新的催化剂。鉴于这项工作需要广泛的科学方法，学生在化学和生物学的界面上接受广泛的跨学科领域的培训，目标是将他们的知识应用于生命过程研究中的新问题和复杂问题。本科阶段的外展活动是优先考虑的，以便在研究生阶段招募更多样化的学生群体。本研究项目采用生物信息学、遗传学和生物化学相结合的方法来阐明牛链霉菌生产β -乙基丝氨酸的生物合成基因。鉴于该官能团的不寻常性质，研究了参与炔烃形成的酶的机制，以阐明它们的功能和选择性，以及它们鉴定可能在合成应用中找到实用的新酶家族的潜力。在验证了β -乙基丝氨酸合成基因后，该途径也在体内测试了其移植到不同宿主生物中的能力。该研究还寻求将末端炔引入基于蛋白质的靶标的未来应用。鉴于这项工作需要广泛的科学方法，学生在化学和生物学界面的广泛跨学科领域进行培训，如生物信息学，酶学，微生物遗传学，分析化学和生物工程，目的是培养学生将他们的知识应用于生命过程研究中的新问题和复杂问题。

项目成果

A family of radical halogenases for the engineering of amino-acid-based products

• DOI: 10.1038/s41589-019-0355-x
• 发表时间: 2019-10-01
• 期刊: NATURE CHEMICAL BIOLOGY
• 影响因子: 14.8
• 作者: Neugebauer, Monica E.;Sumida, Kiera H.;Chang, Michelle C. Y.
• 通讯作者: Chang, Michelle C. Y.

Discovery of a pathway for terminal-alkyne amino acid biosynthesis

• DOI: 10.1038/s41586-019-1020-y
• 发表时间: 2019-03-21
• 期刊: NATURE
• 影响因子: 64.8
• 作者: Marchand, J. A.;Neugebauer, M. E.;Chang, M. C. Y.
• 通讯作者: Chang, M. C. Y.