New Radical SAM Enzymes in Menaquinone Biosynthesis

获得这一奖项后，化学系的生命过程化学项目资助德克萨斯农工大学的Tadhg Begley教授研究细菌中的孟喹酮生物合成的酶学。孟喹酮是一种膜结合维生素，在细菌能量生成和人体血液凝结中发挥关键作用。最近，一条新的途径被发现，说明这种化合物是如何在细菌中产生的。拟议的研究将侧重于了解这一途径所涉及的新化学的细节。这项研究具有重要意义，因为它将揭示细菌中的新化学反应，这将使设计新的抗生素对抗病原菌成为可能。除了在菜籽酮生物合成项目过程中获得的新知识外，研究生和一批重要的本科生将接受生物化学方面的培训。国际生物化学学会还将修订教科书《生物途径的有机化学》，并继续参加一个工作坊，指导有机化学和生物化学的新教师。最近发现了一种新的菜籽酮生物合成途径，它使用两种自由基SAM酶(MqnE和MqnC)来组装辅因子的Napthoquone部分。这两种酶都涉及芳香环的自由基加成反应。将进行一系列实验来阐明这两种酶的作用机制。以物理有机化学为基础的方法将涉及底物类似物的合成和测试，以捕获和表征中间体。序列分析预测了编码该途径上最后两种酶的基因的同一性。还将进行一系列本科项目，以表征这些基因产品。由于孟喹酮是所有生命系统中的重要辅因子，了解这一广泛分布的生物合成途径是生命过程基本化学的一个要素。此外，就长期的科学影响而言，这一途径具有开发抗生素的潜力，因为它在大多数人类肠道细菌中不存在，在许多病原体中存在。

With this award, the Chemistry of Life Processes Program in the Chemistry Division is funding Professor Tadhg Begley from Texas A&M University to investigate the enzymology of menaquinone biosynthesis in bacteria. Menaquinone is a membrane bound vitamin that plays a key role in bacterial energy generation and human blood clotting. Recently a new pathway was discovered for how this compound is produced in bacteria. The proposed research will focus on understanding the details of the new chemistry involved in this pathway. This research is significant because it will uncover new chemical reactions in bacteria that will enable the design of new antibiotics against pathogenic bacteria. In addition to new knowledge gained during the course of the menaquinone biosynthesis project, graduate students and a significant cadre of undergraduates will receive training in biological chemistry. The PI will also revise the textbook "The Organic Chemistry of Biological Pathways" and continue to participate in a workshop to mentor new faculty in organic and biological chemistry. A new menaquinone biosynthetic pathway was recently discovered that uses two radical SAM enzymes (MqnE and MqnC) to assemble the napthoquinone moiety of the cofactor. Both of these enzymes involve radical addition reactions to aromatic rings. A set of experiments to elucidate the mechanisms of these two enzymes will be carried out. The physical organic chemistry-based approach will involve the synthesis and testing of substrate analogs to trap and characterize intermediates. Sequence analysis predicts the identity of the genes encoding the last two enzymes on the pathway. A set of undergraduate projects, to characterize these gene products will also be conducted. As menaquinone is an important cofactor in all living systems, understanding this widely distributed biosynthetic pathway is an element of the basic chemistry of life processes. In addition, in terms of long range scientific impact, this pathway has potential for antibiotic development because it is absent in most human intestinal bacteria and present in many pathogens.