Menaquinone biosynthesis via the futalosine pathway

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形成的必需维生素（维生素K）。维生素K缺乏会导致血液凝固时间延长和老化。有了这个奖项，化学部的生命过程化学计划资助德克萨斯州A M大学（TAMU）的Tadhg Begley博士研究维生素K是如何生物化学合成的。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。除了科学目标外，贝格利博士还将通过指导大草原景观大学的一名学生和教职员工，帮助增加来自不同背景的学生的参与。 贝格利博士还提供研究机会，本科生，并通过每年的得克萨斯州A M大学化学开放的房子与社会参与。 本研究主要集中在对氨基夫他洛辛合酶（MqnE）的完整的机理表征上。这种酶是不寻常的，它将腺苷自由基结合到反应产物中，而不是用它来提取氢原子。利用顺磁共振技术和自由基中间体的捕获，确定了结合捕获自由基的构象。MqnE的机制充当自由基S-腺苷-L-甲硫氨酸（SAM）酶的模型系统，SAM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。这项研究将通过futalosine依赖性途径表征甲萘醌生物合成所需的所有酶，并将开发新的，普遍有用的，研究酶介导的自由基加成苯环的策略。更广泛的影响包括指导学生和教师在草原视图A M大学，一套生物实验的TAMU化学开放日的发展，两个本科生/年的生物化学研究的培训，并在生物辅助因子的国际会议的组织。这个奖项反映了NSF的法定使命，并已被认为是值得通过使用基金会的智力价值和更广泛的影响审查标准进行评估的支持。

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.