Hematopoietic cells have different types of glucose transporters; for example, activation of T cells causes dramatic increases in Glut1 expression to maintain immune homeostasis. Once transported into the cell, glucose is metabolized through different biochemical pathways to provide energy and building blocks for macromolecules that constitute the cell or regulatory metabolites. Glucose can be stored in cells in the form of glycogen, which constitutes a rapid source of energy through its breakdown to free glucose (glycogenolysis), although this pathway is limited to a certain number of hematopoietic cells. Chemotaxins (FMLP, C5ades arg, arachidonic acid) activate granulocytes to catabolize significant amounts of endogenous glycogen.

Glycolysis

Glycolysis is a series of chemical reactions by which six-carbon glucose is converted into two three-carbon keto-acids (pyruvate). Importantly, these oxidative reactions generate energetic molecules such as ATP and NADH and can occur in the absence of oxygen and mitochondria. In some cells, such as erythrocytes, anaerobic glycolysis produces lactate, but in most cell types pyruvate is completely oxidized to acetyl coenzyme-A (acetyl-CoA) and carbon dioxide by the mitochondrial pyruvate dehydrogenase complex and the tricarboxylic acid (TCA) cycle coupled to oxidative phosphorylation. In general, hematopoietic stem cells are thought to largely depend on glycolysis, whereas more differentiated cells, except for erythrocytes, use mitochondrial oxidative metabolism. Glycolytic fluxes are under intrinsically tight control through intermediate metabolites in the pathway. The most powerful control is exerted by fructose 2,6-bisphosphate (F-2,6-BP), which is generated by phosphofructokinase 2. F-2,6-BP allosterically activates phosphofructokinase, providing a “feed-forward” mechanism of stimulation. Activation of growth factor signaling pathways potently stimulates glycolysis at different points, including phosphorylation of phosphofructokinase 2 and pyruvate kinase cell-specific isoforms. The PI3K pathway is a major signaling pathway that controls glycolysis.

Interestingly, in erythrocytes, 1,3-diphosphoglycerate can be diverted from glycolysis to synthesize 2,3-diphosphoglycerate (2,3- DPG) via the enzyme diphosphoglycerate (Rapoport-Laubering shunt). 2,3-DPG is an important metabolite that regulates oxygen binding to hemoglobin; thus increased levels of 2,3-DPG (e.g., under hypoxic conditions) allow hemoglobin to release oxygen under low partial oxygen tensions.

Pentose Phosphate Pathway

The pentose phosphate pathway (PPP) derives from glycolysis in the cytoplasm. The first enzyme in this pathway is glucose-6-phosphate dehydrogenase (G6PDH) and produces NADPH, a substrate used for lipogenesis and glutathione regeneration by glutathione reductase. The regulation of NADPH production through G6PDH is through NADPH-mediated product inhibition. The PPP is also important in generating ribose-5 phosphate, which is a precursor for nucleotide synthesis in proliferating cells. Interestingly, G6PDH deficiency leads to low levels of NADPH, which is essential for con trolling ROS through glutathione reductase. It is one of the most common erythrocyte enzymopathies, and these cells cannot prevent oxidative damage in critical molecules such as heme, causing overall irreparable damage to the cell at a much higher rate than normal, particularly in response to certain environmental triggers such as drugs and stress. The damaged erythrocytes are removed from circulation in the spleen and destroyed by macrophages at an elevated rate, leading to anemia. This enzymopathy occurs in areas with high malarial burden, in part because the mutated recessive allele confers malarial resistance. This resistance is because RBCs with low G6PDH activity, when infected with the parasite, are continuously removed from the circulation.

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مواضيع ذات صلة

 G Protein–Coupled Receptor and Chemokine Signaling

Cytokine Receptors and Janus-Activated Kinase Signaling

Sterile Mutants, Membrane Receptors and G Factors

Isolation of α2 Protein

Silencing HML and HMR

The Expression and Recombination Paradoxes

Receptor Tyrosine Kinases, Phosphoinosite-3-Kinase, and Mitogen-Activated Protein Kinase Pathways

Mating Type Conversion in Saccharomyces cerevisiae

The Yeast Cell Cycle

Structure and Function of TFIIIA

Switching from Oocyte to Somatic 5S Synthesis

Genome Editing of Immune Effector Cells for Safer and More Potent Cancer Therapies (CAR-T Cells)