Oxidoreductase PYROXD1: myopathies, taurine and metallome

It is well known that DNA molecules carry genetic information across generations. DNA contains many units of genetic instructions, called genes. To decode the instructions carried in the genes, cells employ an interesting group of molecules, called transfer RNAs (tRNAs). Importantly, tRNAs are first generated in an immature, non-functional form. To convert tRNAs into functional molecules, cells have developed a large army of enzymes proteins that speed up biological reactions to change, crop, cut, and paste parts of tRNA molecules. Once processed, tRNAs can play their role in decoding our genes. Among other discoveries, our Laboratory is known for identifying a key enzyme in this process, called the tRNA ligase complex (tRNA-LC). What tRNA-LC does is simple: it builds a complete tRNA molecule by gluing two of its pieces together. Interestingly, the tRNA-LC is in fact a very ancient enzyme that was present in very early life forms on Earth, during a time when even oxygen was absent from the atmosphere. Interestingly, oxygen is in fact highly toxic for many enzymes, especially those that use metals to perform their tasks, like the tRNA-LC. We were thus wondering: how could the tRNA-LC survive in modern, oxygen-rich atmosphere? We found out that, to be protected from oxygen, tRNA-LC evolved together with a private guardian: a poorly understood protein with the mysterious name, PYROXD1. PYROXD1 is absolutely essential to protect the tRNA-LC; furthermore, variations in the gene that codes for PYROXD1 lead to severe muscle diseases (myopathies) in humans. We recently revealed an unexpected molecular mechanism that PYROXD1 uses to protect the tRNA-LC. However, we have evidence that PYROXD1 acts beyond tRNA-LC and has other functions in our cells. For example, we now know that PYROXD1 regulates the cellular concentration of taurine, a molecule that displays a myriad of functions including the modification of certain tRNAs. In this project, we will dissect this connection and study if regulation of taurine levels is linked to myopathies. We also found out that the absence of PYROXD1 in cells causes a large misbalance of metal ions. Metal ions lie at the core of almost all biological processes, and thus the role of PYROXD1 in their regulation has very wide implications. Finally, taking advantage of recent developments in structural biology, we will also study the enigmatic ability of PYROXD1 molecules to attach to each other a phenomenon called oligomerization and critical to many human diseases. We will study why, when and where PYROXD1 makes oligomers and what is the relevance of this process for our cells. Overall, we have started from genes and transfer RNAs, but evolution took us towards PYROXD1, and we are excited to demystify this so far very enigmatic, yet essential human protein and reveal its roles in human health and disease.