Collaborative Research: The Chemistry of Riboflavin Biosynthesis

合作研究：核黄素生物合成的化学

• 批准号: 1904480
• 负责人: Graham Moran
• 金额: $ 32.5万
• 依托单位: Loyola University of Chicago
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1904480&HistoricalAwards=false
• 关键词: Collaborative; Research; Chemistry; Riboflavin; Biosynthesis

Riboflavin (Vitamin B2) is essential in all organisms, facilitating biological reactions that include cellular energy production, photosynthesis, DNA repair and response to oxidative stress. With this award, the Chemistry of Life Processes Program in the Chemistry Division provides funding to Dr. Graham Moran (Loyola University Chicago) and Dr. Audrey Lamb (University of Kansas) to study the ways enzymes function to in the critical biosynthesis of riboflavin. This collaborative project will systematically determine detailed molecular structures of and chemical steps catalyzed by these enzymes. The basic science knowledge learned here may provide strategies for the development of antimicrobial drugs. The experiments are the foundation for the training of undergraduate, graduate, and postdoctoral researchers at these two institutions. In addition, Drs. Lamb and Moran collaborate to co-write articles for the American Society of Biochemistry and Molecular Biology magazine ASBMB Today. These OpEd-style articles provide guidance on professional development that may strengthen the scientific community and promote inclusivity.This research project is undertaken to define the structure-function relationships of the enzymes of riboflavin biosynthesis (specifically RibA, RibB, and RibD). Riboflavin biosynthesis includes five enzymatic activities that are unparalleled in nature. This pathway has been studied in sufficient detail to establish the chemical transformations performed by each enzyme and the salient characteristics of the enzymes. The focus of this research is to define the mechanisms of the unusual deformylation reactions of RibA and RibB and the unconventional multi-activity of RibD. The kinetic and chemical mechanistic work (in the steady and pre-steady states) are supported by structural biology investigations (X-ray crystallography). The results provide valuable fundamental knowledge for the field of enzymology and future biocatalysis research.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.

核黄素（维生素B2）在所有生物中都是必不可少的，促进了包括细胞能量产生，光合作用，DNA修复和对氧化应激的反应的生物反应。有了这个奖项，化学部门的化学过程计划为Graham Moran博士（芝加哥洛约拉大学）和Audrey Lamb（堪萨斯大学）提供了资金，以研究酶在核黄素关键生物合成中的酶功能。 该协作项目将系统地确定这些酶催化的详细分子结构和化学步骤。这里学到的基础科学知识可能会为开发抗菌药物提供策略。实验是这两个机构培训本科，研究生和博士后研究人员的基础。 另外，博士。 Lamb and Moran合作为美国生物化学和分子生物学杂志ASBMB的美国生物化学和分子生物学学会合作。这些操作风格的文章为专业发展提供了指导，可以增强科学界并促进包容性。该研究项目是为了定义核黄素生物合成酶的结构 - 功能关系（特别是RIBA，RIBB和RIBD）。 核黄素生物合成包括五种在自然界中无与伦比的酶促活性。已经对该途径进行了足够的详细研究，以建立每种酶进行的化学转化和酶的显着特性。这项研究的重点是定义RIBA和RIBB异常畸形反应的机制以及RIBD的非常规多活动。结构生物学研究（X射线晶体学）支持动力学和化学机械工作（在稳定和稳态的状态下）。该结果为酶学和未来生物催化研究提供了宝贵的基本知识。该奖项反映了NSF的法定任务，并被认为是值得通过基金会的知识分子优点和更广泛的影响评估标准通过评估来支持的。

项目成果

Perturbing the Movement of Hydrogens to Delineate and Assign Events in the Reductive Activation and Turnover of Porcine Dihydropyrimidine Dehydrogenase

扰动氢的运动来描述和分配猪二氢嘧啶脱氢酶的还原激活和周转事件

• DOI: 10.1021/acs.biochem.1c00243
• 发表时间: 2021
• 期刊: Biochemistry
• 影响因子: 2.9
• 作者: Beaupre, Brett A.;Forouzesh, Dariush C.;Butrin, Arseniy;Liu, Dali;Moran, Graham R.
• 通讯作者: Moran, Graham R.

Evidence for the Chemical Mechanism of RibB (3,4-Dihydroxy-2-butanone 4-phosphate Synthase) of Riboflavin Biosynthesis.

• DOI: 10.1021/jacs.2c03376
• 发表时间: 2022-07-20
• 期刊: JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
• 影响因子: 15
• 作者: Kenjic, Nikola;Meneely, Kathleen M.;Wherritt, Daniel J.;Denler, Melissa C.;Jackson, Timothy A.;Moran, Graham R.;Lamb, Audrey L.
• 通讯作者: Lamb, Audrey L.

The Interaction of Porcine Dihydropyrimidine Dehydrogenase with the Chemotherapy Sensitizer: 5-Ethynyluracil

猪二氢嘧啶脱氢酶与化疗增敏剂 5-乙炔尿嘧啶的相互作用

• DOI: 10.1021/acs.biochem.1c00096
• 发表时间: 2021
• 期刊: Biochemistry
• 影响因子: 2.9
• 作者: Forouzesh, Dariush C.;Beaupre, Brett A.;Butrin, Arseniy;Wawrzak, Zdzislaw;Liu, Dali;Moran, Graham R.
• 通讯作者: Moran, Graham R.

An improved method for the expression and purification of porcine dihydropyrimidine dehydrogenase

• DOI: 10.1016/j.pep.2020.105610
• 发表时间: 2020-07-01
• 期刊: PROTEIN EXPRESSION AND PURIFICATION
• 影响因子: 1.6
• 作者: Beaupre, Brett A.;Roman, Joseph, V;Moran, Graham R.
• 通讯作者: Moran, Graham R.

Transient-State Analysis of Porcine Dihydropyrimidine Dehydrogenase Reveals Reductive Activation by NADPH

• DOI: 10.1021/acs.biochem.0c00223
• 发表时间: 2020-07-07
• 期刊: BIOCHEMISTRY
• 影响因子: 2.9
• 作者: Beaupre, Brett A.;Forouzesh, Dariush C.;Moran, Graham R.
• 通讯作者: Moran, Graham R.