Pyruvate kinase M2: A simple molecule with complex functions

Alquraishi, Mohammed; Puckett, Dexter; Alani, Dina; Humidat, Amal S.; Frankel, Victoria; Donohoe, Dallas R.; Whelan, Jay; Bettaieb, Ahmed

doi:10.1016/j.freeradbiomed.2019.08.007

Cited by 115 publications

(108 citation statements)

References 203 publications

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“…Post‐translational modifications of the glycolytic enzyme pyruvate kinase M2 (PKM2), precisely the dimerization of the enzyme under oxidative stress conditions, cause cytoplasm‐to‐nucleus translocation. The enzyme is most active in glycolysis when in tetrameric formation . The ratio of dimeric/tetrameric PKM2 depends on the cell's ROS concentrations.…”

Section: Macrophages From Ra Patients Are Hypermetabolicmentioning

confidence: 99%

“…The mechanism of how hypermetabolic macrophages sustain the production of the pro-inflammatory cytokines IL-1β and IL-6 has been defined. 85 86 The ratio of dimeric/tetrameric PKM2 depends on the cell's ROS concentrations. Hypermetabolic macrophages from CAD patients release more ROS, particularly in the peri-mitochondrial space; resulting in the translocation of the cytoplasmic enzyme into the nucleus.…”

Section: R a T Cell S Mis Pl Ace Amp -Ac Tivated Protein K Ina S Ementioning

confidence: 99%

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Immunometabolism in the development of rheumatoid arthritis

Weyand

Goronzy

2020

Immunological Reviews

114

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In rheumatoid arthritis (RA), breakdown of self‐tolerance and onset of clinical disease are separated in time and space, supporting a multi‐hit model in which emergence of autoreactive T cells is a pinnacle pathogenic event. Determining factors in T cell differentiation and survival include antigen recognition, but also the metabolic machinery that provides energy and biosynthetic molecules for cell building. Studies in patients with RA have yielded a disease‐specific metabolic signature, which enables naive CD4 T cells to differentiate into pro‐inflammatory helper T cells that are prone to invade into tissue and elicit inflammation through immunogenic cell death. A typifying property of RA CD4 T cells is the shunting of glucose away from glycolytic breakdown and mitochondrial processing toward the pentose phosphate pathway, favoring anabolic over catabolic reactions. Key defects have been localized to the mitochondria and the lysosome; including instability of mitochondrial DNA due to the lack of the DNA repair nuclease MRE11A and inefficient lysosomal tethering of AMPK due to deficiency of N‐myristoyltransferase 1 (NMT1). The molecular taxonomy of the metabolically reprogrammed RA T cells includes glycolytic enzymes (glucose‐6‐phosphate dehydrogenase, phosphofructokinase), DNA repair molecules (MRE11A, ATM), regulators of protein trafficking (NMT1), and the membrane adapter protein TSK5. As the mechanisms determining abnormal T cell behavior in RA are unraveled, opportunities will emerge to interject autoimmune T cells by targeting their metabolic checkpoints.

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Section: Macrophages From Ra Patients Are Hypermetabolicmentioning

confidence: 99%

Section: R a T Cell S Mis Pl Ace Amp -Ac Tivated Protein K Ina S Ementioning

confidence: 99%

Immunometabolism in the development of rheumatoid arthritis

Weyand

Goronzy

2020

Immunological Reviews

114

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“…Recent literatures report that pyruvate kinase M2 (PKM2) is a critical determinant of glycolytic reprogramming in macrophage [ 20 ]. Y105 of PKM2 regulates the glycolysis and oxidative phosphorylation via controlling the ration of inactive and active forms of PKM2 [ 21 , 22 ]. Monomer and dimer forms of PKM2, with inactive enzymatic pyruvate kinase activity, promote macrophage glycolysis and inflammatory responses.…”

Section: Introductionmentioning

confidence: 99%

Annexin A5 regulates hepatic macrophage polarization via directly targeting PKM2 and ameliorates NASH

et al. 2020

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Nonalcoholic steatohepatitis (NASH), the progressive form of nonalcoholic fatty liver disease (NAFLD), is becoming a common chronic liver disease with the characteristics of steatosis, inflammation and fibrosis. Macrophage plays an important role in the development of NASH. In this study, Annexin A5 (Anx A5) is identified with the special effect on hepatic macrophage phenotype shift from M1 to M2. And it is further demonstrated that Anx A5 significantly switches metabolic reprogramming from glycolysis to oxidative phosphorylation in activated macrophages. Mechanistically, the main target of Anx A5 in energy metabolism is confirmed to be pyruvate kinase M2 (PKM2). And we following reveal that Anx A5 directly interacts with PKM2 at ASP101, LEU104 and ARG106, inhibits phosphorylation of Y105, and promotes PKM2 tetramer formation. In addition, based on the results of PKM2 inhibitor (compound 3k) and the phosphorylated mutation (PKM2 (Y105E)), it is proved that Anx A5 exhibits the function in macrophage polarization dependently on PKM2 activity. In vivo studies also show that Anx A5 improves steatosis, inflammation and fibrosis in NASH mice due to specially regulating hepatic macrophages via interaction with PKM2. Therefore, we have revealed a novel function of Anx A5 in hepatic macrophage polarization and HFD-induced NASH, providing important insights into the metabolic reprogramming, which is important for NASH therapy.

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“…55 Apart from their biological effects in glycolysis, PKs regulate major cell signalings by phosphorylating key proteins to adjust gene expression in the nucleus. 56 Recently, PKM1 and PKM2, two main subtypes of PKs in the brain tissue, have become hotpots in glioma treatment for its correlation with radiation sensitivity. 57 PKM2 was involved in adapting glioma cells to a different microenvironment through regulating nutrients and growth signaling pathways allosterically.…”

Section: Pyruvate Kinases (Pks)mentioning

confidence: 99%

<p>Emerging Roles and Therapeutic Interventions of Aerobic Glycolysis in Glioma</p>

Han¹,

Shi²,

Cao³

et al. 2020

OTT

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Glioma is the most common type of intracranial malignant tumor, with a great recurrence rate due to its infiltrative growth, treatment resistance, intra-and intertumoral genetic heterogeneity. Recently, accumulating studies have illustrated that activated aerobic glycolysis participated in various cellular and clinical activities of glioma, thus influencing the efficacy of radiotherapy and chemotherapy. However, the glycolytic process is too complicated and ambiguous to serve as a novel therapy for glioma. In this review, we generalized the implication of key enzymes, glucose transporters (GLUTs), signalings and transcription factors in the glycolytic process of glioma. In addition, we summarized therapeutic interventions via the above aspects and discussed promising clinical applications for glioma.

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Pyruvate kinase M2: A simple molecule with complex functions

Cited by 115 publications

References 203 publications

Immunometabolism in the development of rheumatoid arthritis

Immunometabolism in the development of rheumatoid arthritis

Annexin A5 regulates hepatic macrophage polarization via directly targeting PKM2 and ameliorates NASH

<p>Emerging Roles and Therapeutic Interventions of Aerobic Glycolysis in Glioma</p>

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