Studies on Agrocin 84-a "Trojan Horse" tRNA synthetase inhibitor

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Intellectual Merit. A vast number of microbial secondary metabolites have been shown to have antimicrobial properties. The biological functions of these molecules can be complex and reflect the highly complex relationships in which microbes engage. This project focuses on agrocin 84, a bacteriocin, produced by the soil bacterium Agrobacterium radiobacter strain K84. Agrocin 84 targets the plant pathogenic bacterium Agrobacterium tumefaciens, which induces tumors in the plant. Agrocin 84 acts a molecular ?Trojan Horse? by mimicking a plant tumor-derived substrate, and thus gaining access to the interior of the cell, where it is processed into a toxin, TM84. TM84 is a potent inhibitor of leucyl-tRNA synthetase, (LeuRS), an essential enzyme that catalyzes the condensation of a leucine to its cognate tRNA and is responsible for the correct translation of the genetic code. Interestingly, the bacterial source of the toxin, Agrobacterium radiobacter, survives by having an alternative synthetase, AgnB2, that is resistant to TM84. The aims of this project are: to determine how TM84 inhibits LeuRS and to determine the basis for AgnB2 resistance to TM84. The research has the to reveal novel insights into the protein translation machinery and to expand understanding of how microbes interact.Broader Impacts. The project has a major educational goal of increasing underrepresented minority participation in the field of biochemistry. This will be achieved by early exposure of high school and undergraduate students to the science of biochemistry, research experience in the laboratory, and mentorship through programs incorporating lectures, seminars and hands-on research experience in the field of biochemistry. Graduate student training and mentoring will be integrated throughout the research and education plans to enhance professional and scientific development.