Reader Group: How do protein making factories prevent cardiovascular disease? — Radcliffe Department of Medicine (ox.ac.uk)

My main research interest is the protein translation apparatus, with a particular focus on aminoacyl-tRNA synthetases (aaRSs) and tRNAs. AaRSs catalyze the essential first step of protein synthesis by covalently attaching each of the 20 standard amino acids to its cognate tRNA. Research in this area is fundamental to our understanding of the molecular and evolutionary processes that have led to the development and translation of the genetic code.   AaRS function was originally thought to be restricted to protein synthesis but recent research has dramatically changed this viewpoint. Whether it is because of their ancient and ubiquitous nature, catalytic activity or other reasons, evolution has conscripted this family of enzymes into a range of diverse non-canonical functions. These range from biosynthesis of amino acids, antibiotics and tRNA modifications to viral replication and cytokine-like activities in higher eukaryotes.

Our analysis of the non-canonical activities of aaRSs excitingly promises to reveal previously unknown catalytic activities and novel biological functions of these enzymes.   We are also applying these studies towards the creation of novel therapeutics for the treatment of cardiovascular and microbial diseases. One example is our research into the therapeutic potential of a naturally occurring fragment of human tyrosyl-tRNA synthetase (mini-TyrRS), which is a potent inducer of angiogenesis or new blood vessel growth in higher eukaryotes. Such pro-angiogenic molecules have been proposed to be a potential therapeutic strategy to treat patients with peripheral vascular disease such as diabetes or atherosclerosis sufferers as well as in response to myocardial infarction. In collaboration with our long-standing colleague, Dr. Ellie Tzima, we are exploring the molecular mechanism by which mini-TyrRS regulates angiogenesis in vitro and in vivo. 

Another example is our discovery that a naturally occurring antibiotic, known as agrocin 84, specifically targets bacterial leucyl-tRNA synthetases using a previously unknown mechanism. Although components of the translation apparatus are already prominent targets for existing antibiotics, the multitude of essential aaRSs remain a promising and underutilized source of new anti-infectives. We are therefore exploring the possibility of using agrocin 84 as the basis for the development of a novel antibiotic targeting a range of bacteria causing infections in humans.