Modelling of SHMT1 riboregulation predicts dynamic changes of serine and glycine levels across cellular compartments

Abstract

Serine hydroxymethyltransferase (SHMT) regulates the serine-glycine one carbon metabolism and plays a role in cancer metabolic reprogramming. Two SHMT isozymes are acting in the cell: SHMT1 encoding the cytoplasmic isozyme (SHMT1) and SHMT2 encoding the mitochondrial one (SHMT2). Here we present a molecular model built on experimental data reporting the interaction between SHMT1 protein and SHMT2 mRNA, recently discovered in lung cancer cells. Using a stochastic dynamic model, we show that RNA moieties dynamically regulate serine and glycine concentration, shaping the system behaviour. For the first time we observe an active functional role of the RNA in the regulation of the serine-glycine metabolism and availability, which unravels a complex layer of regulation that cancer cells exploit to fine tune aminoacids availability according to their metabolic needs. The quantitative model presented herein exploits RNA molecules as metabolic switches of the SHMT1 activity. Our results pave the way for the development of RNA-based molecules able to unbalance serine metabolism in cancer cells.

Identification of candidate metabolite biomarkers for metabolic syndrome and its five components in population-based human cohorts

“…5). Human serine hydroxymethyltransferases (SHMTs) catalyze the conversion of Ser and Gly and vice versa, a process that is linked to the folate cycle [53,54]. Additionally, the breakdown of Gly by the glycine cleavage system (GCS) is also associated with the folate cycle [55] (Fig.…”