Deacetylation of phosphoglycerate mutase in its distinct central region by SIRT2 down‐regulates its enzymatic activity

Abstract

Substantially high rate of glycolysis, known as the Warburg effect, is a well-known feature of cancers, and emerging evidence suggests that it supports cancerous proliferation/tumor growth. Phosphoglycerate mutase (PGAM), a glycolytic enzyme, is commonly up-regulated in several cancers, and recent reports show its involvement in the Warburg effect. Here, a comprehensive analysis shows that PGAM is acetylated at lysines 100/106/113/138 in its central region, and a member of the Sirtuin family (class III deacetylase), SIRT2, is responsible for its deacetylation. Over-expression of SIRT2 or mutations at the acetylatable lysines of PGAM attenuates cancer cell proliferation with a concomitant decrease in PGAM activity. We also report that the acetyltransferase PCAF (p300/CBP-associated factor) interacts with PGAM and acetylates its C-terminus, but not the central region. As prior evidence suggests that SIRT2 functions as a tumor suppressor, our results would provide support for the mechanistic basis of this activity.

Metabolic control of primed human pluripotent stem cell fate and function by the miR-200c–SIRT2 axis

“…43). However, other studies showed that the same enzyme’s activity is downregulated by SIRT1 or SIRT2 (refs 44,45). In addition, a recent study showed that GAPDH is activated by acetylation of its K254 residue 46 .…”

Dichloroacetic acid (DCA) synergizes with the SIRT2 inhibitor Sirtinol and AGK2 to enhance anti-tumor efficacy in non-small cell lung cancer

“…35 In contrary, Xu et al found that SIRT2 could enhance glycolysis in A549 and MEF cells by targeting PGAM2. 3,36 Wang et al revealed that SIRT2 could inhibit oxidative stress by activating G6PD 2 in HEK293T cells. In the present study, SIRT2 inhibitors were shown to decrease the serine-phosphorylation level of PDHA1, which might result from changing of lysine-acetylation level.…”

p300 is not required for metabolic adaptation to endurance exercise training

“…This is important because reversible acetylation of these enzymes can regulate their activity and, in turn, can regulate metabolic flux (42,45,46). For instance, the glycolytic enzyme, phosphoglycerate mutase, is acetylated by p300/CBP-associated factor, and deacetylation increases its activity (46).…”

“…This is important because reversible acetylation of these enzymes can regulate their activity and, in turn, can regulate metabolic flux (42,45,46). For instance, the glycolytic enzyme, phosphoglycerate mutase, is acetylated by p300/CBP-associated factor, and deacetylation increases its activity (46). Similarly, lysine-to-glutamine mutation (which mimics constitutive acetylation) of the glycolytic enzymes, aldolase B and glycerol-3-phosphate dehydrogenase, inhibits their enzymatic activity, although the KAT that acetylates these proteins is unknown (42).…”