Metabolic networks can often be thought of like electrical circuits. Image credit: John Barkiple (CC0)
The building blocks of all cells are made from a handful of chemical elements, including carbon, nitrogen, sulfur and phosphorus. To grow optimally, cells need to regulate their metabolism – in other words, the biochemical reactions that keep them alive – based on the availability of these elements. As a result, cells have evolved various mechanisms to sense when usable forms of these elements are present.
Proteins are chains of building blocks known as amino acids, which are assembled with the help of molecules called transfer ribonucleic acids, or tRNAs for short. Some of these molecules can be modified by attaching sulfur-containing chemical tags known as thiol groups to make “thiolated tRNAs”. Research has shown that, when there was more of an amino acid known as methionine around, the cells made more thiolated tRNA. These previous studies also suggested that mutant cells lacking thiolated tRNAs might have altered carbon and nitrogen metabolism. Yet, it remained unclear what exactly was leading to this metabolic rewiring.
Now, Gupta et al. have combined several biochemical and genetics approaches to study the role of thiolated tRNAs in yeast. The experiments revealed that mutant cells lacking thiolated tRNAs were unable to properly sense the levels of methionine and other amino acids, which are the cell’s major source of nitrogen. These mutant cells were also found to have a reduced level of phosphorous-containing compounds known as phosphates, which are involved in numerous biological processes.
Gupta et al. showed that reducing the level of phosphates caused carbon that is normally used to make chemicals required for growth to be re-routed towards making carbohydrates to store energy instead. This is similar to what happens when the cells are starving, showing that a ‘squeeze’ on internal phosphates metabolically rewires cells into a state that is like starvation.
These findings show how modified tRNAs can use the availability of amino acids to alter the cell’s metabolism by altering how much phosphate is present. In doing so, the thiolated tRNAs essentially allow the cell to decide whether it has enough of the right nutrients to grow. These findings may also have implications for human health, since errors in coordinating metabolism are responsible for certain medical conditions including several cancers.
Finally, technical challenges mean many questions remain unanswered about how phosphate levels are regulated within cells. These new findings point to a pressing need to understand phosphate metabolism as a prerequisite to better understand how cells regulate their overall metabolism.
