SAICAR, an intermediate of de novo purine nucleotide biosynthesis, selectively activates pyruvate kinase isoform M2 (PKM2) with an EC50 of 0.3 mM.

Upon glucose starvation, the concentration of cellular SAICAR oscillates and enhances PKM2 activity in cancer cells, facilitating survival under glucose-limited conditions. This interaction between SAICAR and PKM2 is crucial, as cancer cells with higher levels of SAICAR (such as adsl-kd cells or those overexpressing PAICS) demonstrate improved survival, whereas cells deficient in PAICS (paics-kd cells) exhibit earlier mortality compared to controls (control-kd cells). Furthermore, the SAICAR-PKM2 complex is instrumental in phosphorylating and activating Erk1/2, thereby increasing PKM2's affinity for SAICAR through subsequent phosphorylation. This complex is also essential for continuous Erk1/2 activation and for promoting mitogen-induced cell proliferation, underscoring the importance of the SAICAR-PKM2 interaction in inducing H3 T11 and Erk1/2 phosphorylation, thereby facilitating cancer cell survival and proliferation in environments with limited glucose availability.