SHMT2 and cancer: Using SHMT1 KO-HAP1 cells to render them uniquely dependent upon mitochondrial SHMT2 enzymatic activity and prevent metabolic compensation by reversal of SHMT1 catalysis (serine → glycine) in response to loss of SHMT2 [47], we decided to preliminarily explore if more physiologically relevant concentrations of metformin could somewhat impact the mitochondrial serine catabolism in cancer cells by culturing cells in the presence of the [U-13C]serine tracer and determining its catabolization to extracellular formate (Figure 5A, [32]).