Cancer Cell 22, 585–600 (2012)

Cancer cells rely on an elevated glycolysis rate for their increased biosynthetic needs. The glycolytic enzyme phosphoglycerate mutase 1 (PGAM1) catalyzes the conversion of 3-phosphoglycerate (3-PG) to 2-PG downstream of most glycolytic reactions that yield biosynthetic precursors. Hitosugi et al. demonstrate that stable knockdown of PGAM1, an enzyme commonly misexpressed in cancer cells, leads to elevated 3-PG and reduced 2-PG in addition to decreasing the rate of glycolysis, flux through the pentose-phosphate pathway (PPP) and anabolic biosynthesis. Using biochemical and structural approaches, they showed that 3-PG can directly bind the active site of the PPP enzyme 6-phosphogluconate dehydrogenase (6PGD) and that 3-PG can compete with 6PGD's substrate for binding. Treatment with methyl-2-PG, a compound converted to 2-PG in cells, rescues glycolytic rates and flux through the PPP in cells with stable knockdown of PGAM1, indicating that 2-PG feeds back on upstream steps. Indeed, they found that treatment with methyl-2-PG also decreased 3-PG. Because 3-PG is a precursor for serine biosynthesis, the authors evaluated the effects of 2-PG on 3-phosphoglycerate dehydrogenase (PHGDH), which converts 3-PG to 3-phosphohydroxypyruvate. 2-PG can promote PHGDH activity in vitro and in cells but only at concentrations higher than those detected in PGAM1 knockdown cells. Taken together, these data indicate that PGAM1 expression controls the amount of 3-PG, which promotes PPP and biosynthesis, and 2-PG, which indirectly controls the amount of 3-PG by regulating PHGDH activity.