Data Availability StatementNot applicable. and proliferation by giving energy for mobile actions and synthesizing the molecular blocks for creation of proteins, nucleotides, and lipids. Metabolic enzymes are in charge of specific chemical substance reactions on metabolites, which occurs under strict rules at particular subcellular places in the metabolic cascades. Metabolic enzymes, such as for example carboxylases, dehydrogenases, lipoxygenases, oxidoreductases, kinases, lyses, and transferases perform an array of catalytic actions and are accountable for a number of mobile functions essential for 186692-46-6 mobile homeostasis and success. Recent literatures possess established that some metabolic enzymes have nonmetabolic actions that are important in the introduction of tumor. These nonmetabolic actions can be split into two classes. Initial, metabolic enzymes that make use of non-metabolites as substrates to catalyze reactions that are specific through the metabolic reactions where these were originally characterized to focus on. For instance, many metabolic enzymes make use of protein as function and substrates 186692-46-6 as proteins kinases to phosphorylate these proteins substrates, regulating diverse features [1] thereby. Second, metabolic enzymes that translocate using their first subcellular compartments to different organelles, where their metabolite items are directly useful for proteins modifications or performing as instrumental regulators for additional proteins. For instance, mitochondrial -ketoglutarate dehydrogenase (-KGDH) that translocates to the nucleus and produces succinyl-coenzyme A (CoA), which is used by the histone acetyltransferase, lysine acetyltransferase 2A (KAT2A), to succinylate histone H3 [2, 3]. In addition, mitochondrial fumarase, when translocated to the nucleus, produces fumarate that inhibits lysine demethylase 2B (KDM2B) histone demethylase activity and enhances the methylation of histone H3 and the repair of damaged DNA [4]. This review summarizes the recent findings regarding these nonmetabolic functions of metabolic enzymes and highlights the implication of these functions in cancer development. Metabolic enzymes function as protein kinases Protein kinases are critical regulators of intracellular signal transduction pathways that mediate various cellular processes in both unicellular and multicellular organisms. They can directly transfer the -phosphate from adenosine triphosphate (ATP) to specific tyrosine (Tyr), serine (Ser), threonine (Thr), and histidine (His) residues on substrate proteins, thereby altering the functions of these substrates. More than 500 protein kinases have been identified in humans, constituting of about 1.7% of all human genes [5]. Recent studies have exhibited that several metabolic enzymes, such as pyruvate kinase M2 (PKM2), phosphoglycerate kinase 1 (PGK1), ketohexokinase-A (KHK-A), hexokinases (HK), nucleoside diphosphate kinase (NDPK or NDK), and 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 4 (PFKFB4), have unexpected protein kinase activities and play significant roles in nonmetabolic cellular functions. These new studies expand the family of protein kinases and provide new insights into the integrated regulation of cell metabolism and other cellular processes. PKM2 Pyruvate kinase (PK) catalyzes the final rate-limiting step of glycolysis and converts phosphoenolpyruvate (PEP) to pyruvate by transferring a phosphate group from PEP to adenosine diphosphate (ADP), producing ATP. It has four isoforms: PKL, PKR, PKM1, and PKM2. PKM2 is usually highly expressed in cancer cells [6]. Besides, although PKM1 has a higher glycolytic activity than PKM2, only the protein kinase activity of PKM2 has been described till present. PKM2 is usually involved in the regulation of gene expression, mitosis, apoptosis, and other critical cellular activities that promote aerobic glycolysis and tumor growth [7C9]. PKM2s protein kinase activity was initially identified from the 186692-46-6 phosphorylation of histone H3 at Thr11 and that of signal transducer and activator of transcription 3 (STAT3) at Tyr705. In the nucleus, PKM2-mediated histone H3 phosphorylation promotes -catenin- and c-Myc-mediated gene expression, which enhances aerobic glycolysis and promotes the proliferation of tumor cells [10C14]. During mitosis, PKM2 binds to the spindle checkpoint protein Bub3 and phosphorylate it at Tyr207 to allow MDNCF the interaction from the Bub3CBub1 complicated with kinetochores, which is vital for the mitotic/spindle-assembly checkpoint, accurate chromosome segregation, and tumorigenesis [15]. PKM2 also phosphorylates myosin light 186692-46-6 string 2 (MLC2) at Tyr118, primes the binding of Rho-associated proteins kinase 2 (Rock and roll2) to MLC2 as well as the?phosphorylation of Rock and roll2CMLC2 organic at Ser15, to permit the relationship between myosin II with actin, which is necessary for the contractile function from the actomyosin organic on the cleavage furrow, conclusion of the cytokinesis procedure, and proliferation of tumor cells [16]. Furthermore, it’s been discovered that in hepatocellular carcinoma (HCC), PKM2 phosphorylates the sterol regulatory element-binding proteins (SREBPs) at Thr59, activates lipid biosynthesis, and promotes the proliferation.