Glycolysis is a key metabolic pathway involving the enzymatic degradation of one molecule of glucose into two molecules of pyruvate or lactate. This catabolic process produces energy either aerobically (in presence of oxygen) or anaerobically (in absence of oxygen). It is also called the Embden-Meyerhof pathway, named after the scientists who elucidated its reactions.
Site and Source of Glucose:
Glycolytic enzymes reside in the cytosol of most body cells. Dietary glucose, produced by carbohydrate digestion, reaches the liver via portal circulation and is distributed to tissues. Glucose enters cells via facilitated transport mechanisms:
- Liver cells uptake glucose independent of insulin via facilitated diffusion.
- Adipocytes, erythrocytes, brain, and muscle cells import glucose via insulin-dependent carrier-mediated transport.
Sequence of Reactions:
Glycolysis consists of eleven enzyme-catalyzed reactions divided into an energy investment phase (first five steps) and an energy extraction phase (last six steps). Energy is consumed initially to activate glucose before ATP production begins.
Key Reactions:
- Hexokinase phosphorylates glucose to glucose-6-phosphate using ATP and Mg2+. This irreversible step traps glucose inside the cell.
- Phosphoglucose isomerase converts glucose-6-phosphate to fructose-6-phosphate (reversible isomerization).
- Phosphofructokinase-1 (PFK-1) phosphorylates fructose-6-phosphate to fructose-1,6-bisphosphate using ATP. This is a major regulatory and irreversible step.
- Aldolase cleaves fructose-1,6-bisphosphate into glyceraldehyde-3-phosphate and dihydroxyacetone phosphate.
- Triose phosphate isomerase converts dihydroxyacetone phosphate into glyceraldehyde-3-phosphate, so two molecules enter subsequent steps.
- Glyceraldehyde-3-phosphate dehydrogenase oxidizes and phosphorylates glyceraldehyde-3-phosphate to 1,3-bisphosphoglycerate, producing NADH.
- Phosphoglycerate kinase transfers a phosphate to ADP forming ATP and 3-phosphoglycerate (substrate-level phosphorylation).
- Phosphoglycerate mutase converts 3-phosphoglycerate to 2-phosphoglycerate.
- Enolase removes water from 2-phosphoglycerate to yield phosphoenolpyruvate (PEP), a high-energy compound.
- Pyruvate kinase transfers phosphate from PEP to ADP producing pyruvate and ATP (irreversible).
- Under anaerobic conditions, lactate dehydrogenase reduces pyruvate to lactate regenerating NAD+ to sustain glycolysis.
Energy Yield:
Aerobic glycolysis results in a net gain of 8 ATP molecules per glucose (4 from substrate-level phosphorylation and 6 from NADH oxidation via respiratory chain). Anaerobic glycolysis yields 2 ATP per glucose as NADH is consumed in lactate formation.
Biological and Medical Importance:
- Glycolysis supplies rapid energy, essential for tissues reliant on anaerobic metabolism like skeletal muscle and erythrocytes.
- Heart relies on aerobic glycolysis; impaired glycolysis contributes to ischemic damage.
- Deficiencies in glycolytic enzymes cause diseases such as pyruvate kinase deficiency leading to hemolytic anemia.
- Glycolysis metabolizes dietary pentoses, fructose, and galactose products.
- Provides intermediates for biosynthesis of lipids and amino acids.
- Glycolytic enzymes vary in parasites and tumors, impacting their metabolism and radiation sensitivity.
Regulation of Glycolysis:
Controlled by allosteric enzymes hexokinase, PFK-1, and pyruvate kinase, which respond to energy needs and metabolites like ATP, AMP, and citrate. Hormonal regulation also modulates enzyme expression and activity (insulin promotes glycolysis).
Inhibitors of Glycolysis:
- Iodoacetate and arsenate inhibit glyceraldehyde-3-phosphate dehydrogenase.
- Fluoride inhibits enolase.
Fate of Pyruvate:
Under aerobic conditions pyruvate converts to acetyl-CoA, entering the TCA cycle. Under anaerobic conditions, it converts to lactate to maintain glycolysis.
Understanding glycolysis highlights cellular energy metabolism crucial for learning pharmacology and pathophysiology in Pharm.D courses.
Detailed Notes:
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