Fig. 4: Non-canonical functions of metabolic enzymes in the cross-talk between metabolism and gene expression.

Regulation of transcription: Phosphofructokinase 1 (PFK1) regulates the transcriptional activity of YAP/TAZ through a mechanism that is dependent on the presence of its allosteric regulator fructose-2,6-bisphosphate (F2,6BP), which is generated by the bifunctional enzyme 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3). In the presence of F2,6BP, PFK1 translocates to the nucleus and acts as a transcriptional co-activator for YAP/TAZ and TEAD to drive the expression of genes involved in proliferation, the epithelial to mesenchymal transition (EMT) and stem cell maintenance. Inhibition of glycolysis promotes the nuclear translocation of enolase 1 (ENO1) and its alternative gene product c-Myc promoter-binding protein 1 (MBP1). Both proteins function as transcriptional repressors to block transcription of the genes coding for Forkhead Box P1 and c-Myc. Regulation of translation: Inhibition of glycolysis also promotes the binding of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) to the mRNA of interferon α (IFNα) to inhibit translation. This mechanism of regulation mediates the regulation of IFNα production by glycolytic flux in activated T cells. In the absence of substrate, thymidylate synthase (TS) and dihydrofolate reductase (DHFR) block translation of their own mRNAs. This mechanism of feedback regulation ensures the availability of the enzyme when substrate levels accumulate. DHF dihydrofolate, THF tetrahydrofolate, 5,10-me-THF 5,10-methylene tetrahydrofolate, dUMP deoxyuridine monophosphate, dTMP deoxythymidine monophosphate