CAREER: Engineered SAM-Dependent Enzymes for Stereoselective Alkylation Reactions

该奖项是根据《2021年美国救援计划法案》(公法117-2)整体资助的。在化学系化学合成计划的支持下，加州大学圣巴巴拉分校的杨阳正在与一个研究生和本科生团队合作，发现和开发用于选择性C-烷基化反应的生物催化剂。酶是一种蛋白质生物催化剂，自然进化为催化化学反应，通常具有良好的化学、区域和立体选择性。这些生物催化剂在异常温和的条件下在水中发挥作用，从而使化学合成能够以更可持续的方式进行。此外，酶很容易利用微生物宿主大规模生产，最近已被开发用于化学制造和药物过程化学。人们希望发现和设计新类型的生物催化剂，以提高效率和选择性来催化合成重要的反应。杨博士和他的学生将利用他们在有机合成、物理有机化学、酶学和蛋白质工程方面的能力，研究和发现用于选择性C-烷基化反应的高效新生物催化剂，α-烷基化反应是一种广泛用于有机化合物合成的过程。与加州大学伯克利分校正在进行的外展项目合作，杨博士将带领实践工作坊，向当地7-12年级的学生介绍化学合成和生物催化的关键概念和应用。结合有机化学、基因组挖掘和蛋白质工程的想法和技术，杨博士和他的学生旨在发现和开发新的生物催化剂，以促进选择性烷基化反应。除了使用有机催化的例子之外，除了有机催化的例子之外，除了使用有机催化的合成用途外，一般的催化不对称C-烷基化反应的方法相对较少。为了应对这一挑战，杨博士和他的团队正在开发一种完全生物催化的平台，该平台由一组经过改造的烷基转移酶组成，可以使用大量和容易获得的烷基化试剂来促进高度立体选择性的烷基化过程。这种生物催化烷基化平台一旦完全开发，有望允许一系列有用的手性构建块被方便地合成。这一努力的更广泛影响包括让来自代表性不足群体的学生亲身接触科学、技术、工程和数学(STEM)职业，以及计划在地方一级和服务不足的社区进行的外展。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

This award is funded in whole under the American Rescue Plan Act of 2021 (Public Law 117-2).With the support of the Chemical Synthesis (SYN) program in the Division of Chemistry, Yang Yang of the University of California-Santa Barbara (UCSB) is working with a team of graduate and undergraduate students to discover and develop biocatalysts for selective C-alkylation reactions. Enzymes are protein biocatalysts that have naturally evolved to catalyze chemical reactions, often with excellent chemo-, regio- and stereoselectivities. These biocatalysts function in water under exceptionally mild conditions, thus allowing chemical synthesis to be carried out in a more sustainable fashion. Furthermore, enzymes are easily produced on a large scale using microbial hosts and have been exploited recently for applications in chemical manufacturing and pharameutical process chemistry. It is desirable to discover and engineer new classes of biocatalysts to catalyze synthetically significant reactions with enhanced efficiency and selectivity. Dr. Yang and his students will exploit their abilities in organic synthesis, physical organic chemistry, enzymology and protein engineering to investigate and discover efficient new biocatalysts for selective C-alkylation reactions, alpha-to a carbonyl group, a process that is widely used in the synthesis of organic compounds. In partnership with ongoing outreach programs at UCSB, Dr. Yang will lead hands-on workshops to introduce local 7-12th grade students to the key concepts and applications of chemical synthesis and biocatalysis.Combining ideas and technologies from organic chemistry, genome mining and protein engineering, Dr. Yang and his students aim to discover and develop new biocatalysts to facilitate selective alkylation reactions. Despite the synthetic utility to these transformation, aside from examples using organocatalysis, there are relatively few general catalytic asymmetric methods for C-alkylation adjacent to a carbonyl group. To address this challenge, Dr. Yang and his group are developing a fully biocatalytic platform consisting of a set of engineered alkyl transfer enzymes to facilitate highly stereoselective alkylation processes using abundant and readily available alkylation reagents. This biocatalytic alkylation platform, once fully developed, is expected to allow for a range of useful chiral building blocks to be synthesized conveniently. Broader impacts of this endeavor include the hands-on exposure of students from underrepresented groups to science, technology, engineering, and mathematics (STEM) careers, as well as planned outreach focused at the local level and on underserved communities.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.