Synthetic Biology Approaches to Selective Amino Acid Modification and Incorporation

选择性氨基酸修饰和掺入的合成生物学方法

• 批准号: 2204014
• 负责人: Michelle Chang
• 金额: $ 52.8万
• 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: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2204014&HistoricalAwards=false
• 关键词: Synthetic; Biology; Approaches; Selective; Amino

With the support of the Chemistry of Life Processes Program in the Chemistry Division, Professor Michelle Chang from the University of California, Berkeley will develop methods for the incorporation of non-canonical amino acids into proteins. Although proteins carry out a broad range of functions in the cell, they are ostensibly made up a limited set of 20 standard amino acids that represent a limited range of chemical functionality compared to what can be utilized by chemists. However, nature also provides many genetically-encoded pathways to produce novel amino acids with unusual functionality that are typically not incorporated into proteins. The proposed research will utilize a pathway discovered by the Chang group that produces amino acids bearing halo, terminal alkene, and terminal alkyne functionality and will develop methods for the incorporation of these amino acids into proteins. The Chang group will further focus on a new bioinformatic strategy to identify novel pathways for biosynthesis of non-standard amino acids by using new marker enzymes known to cluster with genes involved in the biosynthesis of the amino acid itself. Further exploration of these new gene clusters can shed light on the role of non-standard amino acids in metabolism while also providing a tool to expand the diversity of proteins that can be made. This pursuit will allow graduate students and postdoctoral fellows to be broadly trained at the interface of chemistry and biology. This project will also be integrated with an outreach program to introduce K-5 students to concepts at the interface of chemistry and biology, with a focus on green chemistry.This research project focuses on the development of a bioinformatic strategy to identify novel pathways for biosynthesis of non-standard amino acids. Professor Michelle Chang and her research team will use a resistance marker to identify a wide range of gene clusters that seemingly encode the biosynthesis of new amino acids and related natural products. These gene clusters and their products will be characterized. The new knowledge will be used to expand the scope of non-standard amino acids that can be produced enzymatically. Such an approach promises to open up the possibility of introducing malleable new chemical functionalities, including alkene and alkyne groups, into targeted positions in tailored proteins. The study of the resistance enzymes will provide insight in the recognition of non-standard amino acids and will be used to design tools for residue-selective incorporation of the non-proteinogenic amino acids.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

在化学过程的化学过程中的支持下，加利福尼亚大学的米歇尔·张教授将开发将非典型氨基酸掺入蛋白质中的方法。尽管蛋白质在细胞中具有广泛的功能，但表面上是有限的20个标准氨基酸组组成的，这些氨基酸代表有限的化学功能范围，而化学家可以使用的化学功能。然而，自然还提供了许多遗传编码的途径，以产生具有不寻常功能的新型氨基酸，通常不掺入蛋白质中。拟议的研究将利用Chang组发现的途径，该途径产生了带有光环，末端烯烃和末端炔烃功能的氨基酸，并将开发将这些氨基酸掺入蛋白质中的方法。 Chang组将进一步关注一种新的生物信息学策略，以通过使用已知可与涉及氨基酸生物合成的基因聚集的新标记酶来鉴定非标准氨基酸生物合成的新途径。对这些新基因簇的进一步探索可以阐明非标准氨基酸在代谢中的作用，同时还提供了一种工具来扩大可以制造的蛋白质的多样性。这种追求将使研究生和博士后研究员可以在化学和生物学界面进行广泛的培训。该项目还将与外展计划集成，以向K-5学生介绍化学和生物学界面的概念，重点是绿色化学。该研究项目着重于制定生物信息学策略，以识别非标准氨基酸生物合成的新颖途径。米歇尔·张（Michelle Chang）教授和她的研究团队将使用阻力标记来确定各种基因簇，这些基因簇似乎编码了新的氨基酸和相关天然产品的生物合成。这些基因簇及其产品将被表征。新知识将用于扩大可以通过酶促生产的非标准氨基酸的范围。 这种方法有望开放将可延展的新化学功能（包括烷烃和炔烃组）引入量身定制蛋白质的靶向位置的可能性。对抗性酶的研究将提供识别非标准氨基酸的见解，并将用于设计用于残留的非蛋白质生成氨基酸的残留选择性掺入的工具。这项奖项反映了NSF的法定任务，并被认为是通过该基金会的知识分子的智力和广泛影响来评估的，这是值得通过评估的支持。