Menaquinone biosynthesis via the futalosine pathway

通过氟他洛辛途径进行甲萘醌生物合成

• 批准号: 1905336
• 负责人: Tadhg Begley
• 金额: $ 54万
• 依托单位: Texas A&M University
• 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 2022-07-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1905336&HistoricalAwards=false
• 关键词: Menaquinone; biosynthesis; via; futalosine; pathway

In humans and other mammals, menaquinone is an essential vitamin (vitamin K) involved in blood clotting and bone formation. Vitamin K deficiency leads to prolonged blood clotting times and hemorrhaging. With this award, the Chemistry of Life Processes Program in the Chemistry Division is funding Dr. Tadhg Begley from Texas A&M University (TAMU) to study how vitamin K is biochemically synthesized. The reaction will be tracked over time in order to determine the unique chemical mechanisms of two enzymes involved in the biosynthetic pathway. The resulting basic scientific knowledge may help in the design and discovery of new antibiotics targeting several human pathogens. In addition to the scientific goals, Dr. Begley will help to increase the participation of students from diverse backgrounds by mentoring a student and faculty member at Prairie View A&M University. Dr. Begley also provides research opportunities to undergraduates and engages with the community through the annual Texas A&M University Chemistry open house. The research studies focus on the complete mechanistic characterization of aminofutalosine synthase (MqnE). This enzyme is unusual in incorporating an adenosyl radical into the reaction product rather than using it to abstract a hydrogen atom. The studies determine the conformation of the bound captodative radical by Electron Paramagnetic Resonance and the trapping of radical intermediates. The mechanism of MqnE serves as a model system for radical S-adenosyl-l-methionine (SAM) enzymes that generate a substrate radical by radical addition rather than by hydrogen atom abstraction. MqnC catalyzes a spirocyclization reaction and is also a radical SAM enzyme. MqnD catalyzes the formation of the dihydro-napthoquinone moiety of menaquinone. Reaction product characterization differentiates the two proposed mechanisms for this reaction. This research will characterize all of the enzymes required for the biosynthesis of menaquinone via the futalosine-dependent pathway, and will develop of new, generally useful, strategies for studying enzyme-mediated radical additions to benzene rings. The broader impacts include the mentoring of students and faculty members at Prairie View A&M University, the development of a set of biological experiments for the TAMU Chemistry open house, the training of two undergraduates/year in biological chemistry research, and the organization of the international conference on biological cofactors.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.

在人类和其他哺乳动物中，甲基萘醌是一种参与血液凝固和骨骼形成的必需维生素（维生素 K）。维生素 K 缺乏会导致凝血时间延长和出血。凭借该奖项，化学部的生命过程化学项目正在资助德克萨斯农工大学 (TAMU) 的 Tadhg Begley 博士研究维生素 K 的生物化学合成过程。该反应将随着时间的推移进行跟踪，以确定参与生物合成途径的两种酶的独特化学机制。由此产生的基础科学知识可能有助于设计和发现针对几种人类病原体的新抗生素。除了科学目标之外，贝格利博士还将通过指导 Prairie View A&M 大学的学生和教职员工来帮助增加来自不同背景的学生的参与。 贝格利博士还为本科生提供研究机会，并通过年度德克萨斯农工大学化学开放日与社区互动。 研究重点是氨基呋他洛辛合酶 (MqnE) 的完整机制表征。这种酶的不同寻常之处在于将腺苷自由基掺入反应产物中，而不是用它来提取氢原子。这些研究通过电子顺磁共振和自由基中间体的捕获确定了结合的捕获自由基的构象。 MqnE 的机制可作为自由基 S-腺苷-L-甲硫氨酸 (SAM) 酶的模型系统，该酶通过自由基加成而不是通过氢原子提取产生底物自由基。 MqnC 催化螺环化反应，也是一种自由基 SAM 酶。 MqnD 催化甲基萘醌的二氢萘醌部分的形成。反应产物表征区分了该反应的两种拟议机制。这项研究将表征通过氟他洛辛依赖性途径生物合成甲萘醌所需的所有酶，并将开发新的、普遍有用的策略来研究酶介导的苯环自由基加成。更广泛的影响包括对 Prairie View A&M 大学的学生和教职员工进行指导、为 TAMU 化学开放日开发一套生物实验、每年对两名本科生进行生物化学研究培训，以及组织生物辅助因子国际会议。该奖项反映了 NSF 的法定使命，并通过利用基金会的智力优势和更广泛的评估进行评估，认为值得支持。 影响审查标准。

项目成果

Menaquinone Biosynthesis: The Mechanism of 5,8-Dihydroxy-2-naphthoate Synthase (MqnD)

甲萘醌生物合成：5,8-二羟基-2-萘甲酸酯合酶 (MqnD) 的机制

• DOI: 10.1021/acs.biochem.1c00257
• 发表时间: 2021
• 期刊: Biochemistry
• 影响因子: 2.9
• 作者: Manion-Sommerhalter, Hannah R.;Fedoseyenko, Dmytro;Joshi, Sumedh;Begley, Tadhg P.
• 通讯作者: Begley, Tadhg P.

Radical SAM Enzyme HydE Generates Adenosylated Fe(I) Intermediates En Route to the [FeFe]-Hydrogenase Catalytic H-Cluster

• DOI: 10.1021/jacs.0c03802
• 发表时间: 2020-06-17
• 期刊: JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
• 影响因子: 15
• 作者: Tao, Lizhi;Pattenaude, Scott A.;Britt, R. David
• 通讯作者: Britt, R. David

Menaquinone Biosynthesis: Biochemical and Structural Studies of Chorismate Dehydratase

• DOI: 10.1021/acs.biochem.9b00105
• 发表时间: 2019-04-09
• 期刊: BIOCHEMISTRY
• 影响因子: 2.9
• 作者: Mahanta, Nilkamal;Hicks, Katherine A.;Begley, Tadhg P.
• 通讯作者: Begley, Tadhg P.

Menaquinone Biosynthesis: New Strategies to Trap Radical Intermediates in the MqnE-Catalyzed Reaction

• DOI: 10.1021/acs.biochem.1c00181
• 发表时间: 2021-05-17
• 期刊: BIOCHEMISTRY
• 影响因子: 2.9
• 作者: Joshi, Sumedh;Fedoseyenko, Dmytro;Begley, Tadhg P.
• 通讯作者: Begley, Tadhg P.