Pyruvate Kinase M2: A Potential Target for Regulating Inflammation

Abstract

Pyruvate kinase (PK) is the enzyme responsible for catalyzing the last step of glycolysis. Of the four PK isoforms expressed in mammalian cells, PKM2 has generated the most interest due to its impact on changes in cellular metabolism observed in cancer as well as in activated immune cells. As our understanding of dysregulated metabolism in cancer develops, and in light of the growing field of immunometabolism, intense efforts are in place to define the mechanism by which PKM2 regulates the metabolic profile of cancer as well as of immune cells. The enzymatic activity of PKM2 is heavily regulated by endogenous allosteric effectors as well as by intracellular signaling pathways, affecting both the enzymatic activity of PKM2 as a PK and the regulation of the recently described non-canonical nuclear functions of PKM2. We here review the current literature on PKM2 and its regulation, and discuss the potential for this protein as a therapeutic target in inflammatory disorders.

RBM4 Regulates Neuronal Differentiation of Mesenchymal Stem Cells by Modulating Alternative Splicing of Pyruvate Kinase M

“…In cancer cells, transcriptional activation and a splice isoform switch lead to an increase in the expression of PKM2, which not only contributes to intricate metabolic reprogramming but also acts as a transcriptional activator (18). In most of the developing mouse tissues we examined, we observed a gradual Pkm isoform switch toward Pkm1 (Fig.…”

“…PKM2 is expressed in embryonic and tumor cells. PKM2 contributes to intricate metabolic reprogramming via the monomer-dimertetramer interconversion, and it also can transcriptionally modulate gene expression (18). In contrast, PKM1 essentially promotes OXPHOS in energy-consuming tissues, such as brain and muscle (19).…”

Residual pyruvate kinase activity in PKLR‐deficient erythroid precursors of a patient suffering from severe haemolytic anaemia

“…PK‐L and PK‐R are expressed in liver and RBCs. PKM1 is found in tissues with increased catabolic demand such as muscle and brain, whereas PKM2 expression is associated with anabolic function as is found in proliferating and cancer cells . In RBCs, tetrameric PK‐R is allosterically activated by phosphoenolpyruvate and fructose‐1,6‐bisphosphate (FBP) and is deactivated by ATP .…”

Pyruvate controls the checkpoint inhibitor PD-L1 and suppresses T cell immunity

“…Under conditions of high glycolytic activity, when cellular levels of the PKM2 activator fructose 1,6-bisphosphate (FBP) are high, respiration is partially suppressed, and pyruvate is promptly converted into lactate. In contrast, when PKM2 is partially inactivated, most prominently so in cancer cells and inflammatory macrophages (24,(48)(49)(50), upstream glycolytic intermediates accumulate and fuel synthetic pathways, such as the pentose phosphate pathway (PPP), thereby enabling cellular growth and expansion. Although the mechanism is not understood, PKM2 lo activity also makes pyruvate available to the mitochondria, fostering oxidative phosphorylation and TCA cycle activity.…”