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。这项研究旨在探索和发现新的生物合成途径，使罕见的，但有用的官能团，如炔。到目前为止，只有一个机制的炔形成已被确定。相比之下，土壤微生物产生一种新的末端炔氨基酸家族，但其途径尚不清楚。确定和表征生物合成途径可能会提供有关化学结构（如烯烃和炔烃）如何在酶活性位点形成的新知识。有了这个奖项，化学部的生命过程计划的化学资助博士。Michelle Chang研究β-es生物合成的途径。 鉴于这一途径中涉及的不寻常的转换，负责这些反应的酶进行了详细研究，以明确定义其作用机制。 了解它们的反应性可以允许应用，包括标记靶蛋白以在细胞中成像和修饰酶以制造新的催化剂。鉴于这项工作所需的广泛的科学方法，学生在化学和生物学的接口广泛的跨学科领域进行培训，目的是将他们的知识应用于生命过程研究中的新的和复杂的问题。 在本科层次的推广活动，优先招募一个更多样化的学生团体在研究生studys.This研究项目进行澄清的生物合成基因参与生产的β-乙炔丝氨酸在链霉菌cattleya使用生物信息学，遗传学和生物化学方法相结合。鉴于不寻常的性质的官能团，参与形成的炔的酶的机制进行了研究，以阐明它们的功能和选择性，以及它们的潜力，用于识别新的家庭的酶，可能会发现在合成应用中的效用。在验证了β-乙炔基丝氨酸合成的基因后，还在体内测试了该途径移植到不同宿主生物体中的能力。 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。 鉴于这项工作所需的科学方法的广泛范围，学生在化学和生物学的接口，如生物信息学，酶学，微生物遗传学，分析化学和生物工程的目标，培养学生将他们的知识应用于生命过程研究中的新的和复杂的问题。

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.