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Glycolysis (Aerobic and Anaerobic) : Steps, Warburg Effect, Regulation, Energetics, PDH Complex
Glycolysis breaks a glucose molecule down to two molecules of pyruvate.
All reactions of glycolysis occur in the cytoplasm.
Two steps of glycolysis produce ATP through substrate-level phosphorylation; the ATP-producing reactions are catalyzed by phosphoglycerate kinase and pyruvate kinase.
Phosphoglycerate kinase and pyruvate kinase are able to produce ATP because their substrates, 1,3-bisphosphoglycerate and phosphoenolpyruvate, respectively, contain high-energy phosphate groups.
A reaction catalyzed by phosphoglycerate kinase is reversible under physiologic conditions.
The three rate-limiting reactions of glycolysis are catalyzed by hexokinase, phosphofructokinase, and pyruvate kinase; these steps are highly regulated.
Glucokinase is an isozyme of hexokinase found in certain cells, like pancreatic islet cells and hepatocytes, that functions as a glucose sensor for these cells.
PFK-1 is allosterically stimulated by AMP and fructose-2,6-bisphosphate and allosterically inhibited by ATP and citrate.
Fructose-2,6-bisphosphate is synthesized from fructose-6-phosphate by PFK-2 and degraded by FBPase-2, which is part of an enzyme complex with PFK-2.
Glucagon signaling in the liver causes phosphorylation of PFK-2/FBPase-2 via cAMP and PKA, leading to predominance of FBPase-2’s effect, causing decreased levels of F2,6BP and decreased stimulation of PFK-1.
Epinephrine signaling in the heart also causes increases in intracellular cAMP and PKA activity, but the isozyme of PFK-2/FBPase-2 in the heart is phosphorylated at a different site, such that phosphorylation causes predominance of PFK-2 activity, causing increased F2,6BP and stimulating PFK-1.
Increase in intracellular cAMP concentration and the resulting increase in PKA activity also leads to phosphorylation and deactivation of pyruvate kinase.
Insulin influences glycolysis by activating protein phosphatases, which dephosphorylate intracellular enzymes, stimulating glycolysis.
Insulin also induces production of glucokinase in hepatocytes and pancreatic islet cells.
Individuals with uncontrolled diabetes have a relative deficiency of insulin signaling in hepatocytes, leading to predominance of glucagon signaling; this causes persistently elevated cAMP levels and PKA activity, which suppresses glycolysis and encourages gluconeogenesis.
Pyruvate can be metabolized aerobically via the TCA cycle if oxygen and functional mitochondria are present.
In the absence of oxygen or functional mitochondria, pyruvate is anaerobically metabolized by lactate dehydrogenase to lactate.
Pyruvate conversion to lactate produces NAD+, which is an essential cofactor for a glycolytic enzyme, thereby allowing glycolysis to continue.
Erythrocytes regularly produce lactate from glycolysis because they lack mitochondria.
Tumor cells often produce lactate from glycolysis because of changes in enzyme expression and signaling patterns that cause them to prioritize use of hydrocarbon skeletons for anabolic reactions rather than energy production (the Warburg effect).
2,3-Bisphosphoglycerate is a side product of glycolysis produced in erythrocytes by bisphosphoglycerate mutase from 1,3-bisphosphoglycerate.
2,3-BPG decreases hemoglobin’s affinity for oxygen, making it easier for erythrocytes to deliver oxygen to tissues.
Defects in glycolytic enzymes disproportionately affect cells that depend on glycolysis for energy, like erythrocytes.
Erythrocytes of individuals with glycolytic enzyme defects like pyruvate kinase deficiency are unable to run the Na+-K+-ATPase, leading to intracellular accumulation of sodium and hemolytic anemia.
Hemolytic anemia leads to increased levels of indirect (or unconjugated) bilirubin in the serum, which predisposes to bilirubin gallstones.
Individuals with pyruvate kinase deficiency have build-ups of glycolytic intermediates like 1,3-BPG, which is shunted down its other metabolic path through bisphosphoglycerate mutase to produce 2,3-BPG; high levels of 2,3-BPG in pyruvate kinase deficiency improve erythrocytes’ ability to deliver oxygen to tissues, so anemic symptoms are generally milder than anticipated in pyruvate kinase deficiency.
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