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Abnormal Red Cell Metabolism
Published in Harold R. Schumacher, William A. Rock, Sanford A. Stass, Handbook of Hematologic Pathology, 2019
This patient has pyruvate kinase deficiency. Several hereditary red cell enzyme defects can result in nonspherocytic hemolytic anemia. Common among those are G6PD, pyruvate kinase (PK), and hexose kinase (HK) deficiencies. Osmotic fragility is normal in all of the above deficiencies. Autohemolysis test after 48-hr incubation is often abnormal in PK deficiency and HK deficiency. However, the abnormality is corrected with glucose or ATP in HK deficiency, and with ATP only in PK deficiency. The defect should be confirmed by quantitative enzyme levels. Splenectomy should be reserved only for serious cases: It is not curative, but it reduces the transfusion requirement.
Human Erythroenzymopathies Of The Anaerobic Embden-Meyerhof Glycolytic And Associated Pathways
Published in Ronald L. Nagel, Genetically Abnormal Red Cells, 2019
Ernst R. Jaffé, William N. Valentine
The hemolytic anemia is moderately severe and, like that of pyruvate kinase deficiency, nonspherocytic in type. It may be exacerbated by myelosuppressive events such as infection. No evidence has been documented of significant improvement from splenectomy. Red cell TPI activity is reduced to a small fraction of that normally present, and the erythrocyte DHAP is increased some 20- to 40-fold.64 Leukocyte TPI is also greatly reduced, and clinically increased susceptibility to infection has been frequently noted. Despite this, granulocyte function tests, including nitroblue tetrazolium reduction, chemotaxis, and the “respiratory burst” on ingesting microorganisms, have been uniformly normal.61,65
Historical Background
Published in D. B. Keech, J. C. Wallace, Pyruvate Carboxylase, 2018
The enzymes involved in this pathway are: (a) pyruvate kinase, (b) malic enzyme, (c) malate dehydrogenase, and (d) phosphoenolpyruvate (PEP) carboxykinase. The equilibrium between malate and fumarate (e) is catalyzed by fumarase.
Panax notoginseng saponins (PNS) attenuate Th17 cell differentiation in CIA mice via inhibition of nuclear PKM2-mediated STAT3 phosphorylation
Published in Pharmaceutical Biology, 2023
Mei-Yu Shen, Yu-Xi Di, Xiang Wang, Feng-Xiang Tian, Ming-Fei Zhang, Fei-Ya Qian, Bao-Ping Jiang, Xue-Ping Zhou, Ling-Ling Zhou
Pyruvate kinase (PK), a key enzyme of glycolysis, is at the final step of glycolysis and converts phosphoenolpyruvate (PEP) to pyruvate. PK has four isoforms which are distributed in different cell types. Immune cells preferentially express the isoforms PKM1 and PKM2, and PKM2 is apt to express in proliferating cells and is subject to complex allosteric regulation that controls its enzymatic activity (Israelsen and Vander Heiden 2015). In general, PKM2 is present in cells as a tetrameric or dimeric protein. Tetrameric PKM2 locates in the cytoplasm that is highly active enzymatically and efficiently converts PEP to pyruvate. In recent years, non-metabolic functions of dimeric PKM2 have been discovered, such as translocating into the nucleus and regulating gene expression and protein kinase activity (Dong et al. 2016). In particular, dimeric PKM2 was shown to translocate into the nucleus to activate STAT3 in CD4+T cells, macrophages, and cancer cells (Ma et al. 2019; Damasceno et al. 2020; Hou et al. 2020). However, the potential mechanisms of PKM2 in T cell activation and differentiation remain unclear. Recent studies reported that inducing PKM2 tetramerization and blocking its nuclear translocation could strongly inhibit CD4+T cell activation and pathogenicity (Angiari et al. 2020), and the expression of PKM2 is associated with Th17 cell differentiation (Seki et al. 2020). Therefore, regulating PKM2 conformation to suppress Th17 cell differentiation may be a promising therapeutic strategy for RA.
Emerging drug targets for sickle cell disease: shedding light on new knowledge and advances at the molecular level
Published in Expert Opinion on Therapeutic Targets, 2023
Other treatments aim to reduce the propensity of HbS to polymerize. Compounds to increase oxygen affinity of HbS and thereby prevent polymerization have been studied for some time and continue to provide a focus of interest. The newly licensed voxelotor works in this way and does raise circulating Hb levels, but doubts remain about its clinical utility, with concern that the reduction in oxygen unloading might offset any potential gains. Others continue to be of interest in clinical trials [229]. A modification of this approach is the use of peptides and other small molecules to target the cohesive points between neighboring HbS molecules, rather than to increase oxygen affinity per se, but, as yet, none have progressed to clinical trials. Lastly, there is also emerging evidence that pyruvate kinase activators may be helpful by increasing hemoglobin levels via the reduction of erythrocyte 2,3-DPG concentration, together with increased ATP levels, leading to reduced complications of anemia and improved red cell health. Mitapivat and etavopivat both act in this way and are entering early-phase clinical trials. Recent reports of beneficial clinical responses to these reagents is encouraging.
An evaluation of mitapivat for the treatment of hemolytic anemia in adults with pyruvate kinase deficiency
Published in Expert Review of Hematology, 2022
Andrew B. Song, Hanny Al‐Samkari
Pyruvate kinase deficiency (PKD) is a hereditary red blood cell (RBC) disorder that causes chronic hemolytic anemia. PKD was first discovered in the 1960s through a series of seminal studies clarifying the link between glycolysis, hemolytic anemia, and the specific deficiency of the pyruvate kinase enzyme [1–4]. We now understand that the pathogenesis of PKD is due to autosomal recessive mutations in the PKLR gene encoding the RBC pyruvate kinase enzyme. There are four PK isoenzymes in total: the PKLR gene encodes the L (liver) and R (RBC) isoenzymes, while the PKM gene encodes the M1 and M2 (muscle) isoenzymes. As the final enzymatic step in glycolysis, the PK enzyme catalyzes conversion of phosphoenolpyruvate (PEP) to pyruvate. Because mature RBCs are not capable of aerobic metabolism and largely rely on glycolysis for critical anaerobic generation of ATP, abnormalities in PK activity result in RBC ATP deficiency causing RBC dehydration, loss of cell membrane plasticity, and ultimately premature destruction by hemolytic anemia and ineffective erythropoiesis. Reticulocytes are exceptionally susceptible to dehydration and injury in the hypoxic spleen due to the transition from oxidative phosphorylation to glycolysis requiring large amounts of ATP [5].