Glycolysis and Sugar Entry into Cells

Glycolysis Overview

• Glycolysis is the anaerobic oxidation of glucose, converting a six-carbon sugar into 2 three-carbon molecules of pyruvate/lactate
• This process yields a modest amount of ATP (2 ATP).
• Under aerobic conditions, the pyruvate from glycolysis proceeds to complete oxidative degradation into CO2 and H2O through the citric acid cycle and electron transport chain
• Glycolysis is crucial for red blood cell viability, as these cells lack mitochondria
• If ATP production from glycolysis in red blood cells is insufficient, premature cell death and hemolytic anemia can occur
• Complete glucose oxidation requires glycolysis, the citric acid cycle, oxidative phosphorylation, and pyruvate dehydrogenase (PDH) as a connecting reaction.
• Basal metabolism entails hydrolyzing roughly 100 moles of ATP per day, despite the body only containing less than 0.2 moles of ATP.

How Sugars Enter Cells

• Dietary carbohydrates enter the body as disaccharides, starch (amylose and amylopectin), and glycogen
• Sodium-glucose co-transporters (SGLT1, 2, 3) facilitate transport of monosaccharides and disaccharides across the plasma membrane.
• GLUT1: High-affinity transporter located in brain capillaries and red blood cells.
• GLUT2: Low-affinity transporter found in the liver, pancreatic beta cells, and the gut's luminal membrane.
• GLUT3: High-affinity glucose transporter present in the brain and testes.
• GLUT4: Insulin-sensitive transporter located in skeletal muscle, the heart, and adipose cells.
• Glucose transport kinetics into cells are governed by facilitated diffusion.

Glucose Oxidation Process

• Glycolysis converts one glucose molecule into two pyruvate/lactate molecules and generates two ATP molecules
• The glycolytic pathway consists of ten enzymatic reactions, with irreversible steps catalyzed by enzymes 1, 3, and 10 playing a key role in regulating the pathway's flux
• Sustaining glucose flux through glycolysis requires a continuous supply of NAD+
• When one mole of glucose is converted to two moles of pyruvate, two moles of ATP and two moles of NADH are produced
• Phosphorylation of glucose is catalyzed by tissue-specific kinases such as glucokinase (GK) or hexokinase (HX).

Pathway Regulation

• Glycolytic flux adjusts to meet cellular needs, aligning with the rate of ATP consumption.
• AMP activates PFK-1 in glycolytic muscle fibers
• Flux can increase over 100-fold rapidly
• Adenylate kinase converts 2 ADP into an ATP and an AMP molecule if ADP builds up.
• Glycolytic flux in hepatocytes is hormonally regulated, with phosphofructokinase-2/fructose-2,6-bisphosphatase (PFK-2) as the key regulatory enzyme in the liver

Fructose and Galactose Oxidation

• Fructose metabolism differs in muscle and liver tissue.
• In muscle, hexokinase phosphorylates fructose to fructose-6-phosphate (F6P).
• In the liver, fructokinase phosphorylates fructose.
• Hereditary fructose intolerance, or classical fructose intolerance, results from a deficiency in aldolase B
• A deficiency in aldolase B leads to accumulation of fructose-1-phosphate within cells, trapping inorganic phosphate and disrupting cellular processes, leading to symptoms like hypoglycemia and liver damage.
• Galactosemia: An inherited disorder of galactose metabolism.
• Accumulated Gal-1-P interferes with phosphate and glucose metabolism, potentially causing widespread tissue damage, organ failure, and mental retardation.

The 2,3-BPG Shunt

• In red blood cells, a portion of 1,3-BPG is diverted into a shunt to produce 2,3-BPG, altering oxygen binding to hemoglobin and stabilizing its low-oxygen affinity state

Clinical Case

• Pyruvate kinase (PK) deficiency is a genetic disorder leading to rapid breakdown of red blood cells resulting in chronic hemolytic anemia

Key Points

• Glycolysis is a metabolic pathway common to all cells, producing all energy in red blood cells
• Glycolysis converts glucose into two three-carbon molecules of lactate.
• Glycolysis provides metabolites that feed into other metabolic pathways.
• Key regulatory enzymes in glycolysis include hexokinase/glucokinase, phosphofructokinase, and pyruvate kinase.