Medical Biochemistry: Glycolysis and Regulation

Major Pathways of Carbohydrate Metabolism

• Glucose is the central molecule of carbohydrate metabolism
• Major pathways of carbohydrate metabolism begin or end with glucose
• These pathways include:
  • Utilization of glucose as a source of energy
  • Gluconeogenesis from non-carbohydrate precursors
  • Storage of glucose as glycogen
  • Release of glucose from glycogen
  • Pentose phosphate pathway for production of NADPH
  • Use of glucose in glucuronic acid pathway for drug detoxification

Overview of Glycolysis

• Glycolysis is the breakdown of glucose to provide energy (in the form of ATP) and intermediates for other metabolic pathways
• Glycolysis is the principal route for carbohydrate metabolism
• Glycolysis provides ATP in the absence of oxygen, allowing skeletal muscle to perform at high levels of work output when oxygen supply is insufficient
• Diseases in which enzymes of glycolysis are deficient are mainly seen as hemolytic anemias or fatigue

Stages of Glycolysis

• Phosphorylation stage: glucose is converted to glucose-6-phosphate using ATP
• Splitting stage: aldolase and isomerase reactions occur
• Oxido-Reduction stage: ATP is produced by substrate-level phosphorylation

Regulation of Glycolysis

• Hexokinase: phosphorylates glucose to glucose-6-phosphate, inhibited by glucose 6-phosphate, and has a high affinity for glucose
• Glucokinase: phosphorylates glucose to glucose-6-phosphate in liver parenchymal cells and β cells of the pancreas, has a lower affinity for glucose, and functions as a glucose sensor
• 6-Phosphofructo-1 kinase: a regulatory enzyme of glycolysis, inhibited by ATP and activated by fructose 2,6-bisphosphate
• Pyruvate kinase: activated by fructose 1,6-bisphosphate, and inactivated by phosphorylation by a cAMP-dependent protein kinase

Pyruvate Kinase Deficiency

• A rare genetic disorder that causes hemolytic anemia and associated complications
• Symptoms may range from mild to severe, and may include an enlarged spleen, excess iron in the blood, and gallstones
• Severe cases can be life-threatening in infancy and may require regular blood transfusions to survive

Lactate Formation in Muscle

• In exercising skeletal muscle, NADH production exceeds the oxidative capacity of the respiratory chain, leading to an elevated NADH/NAD+ ratio and favoring the reduction of pyruvate to lactate
• Lactate accumulates in muscle, causing a drop in intracellular pH, potentially resulting in cramps
• Lactate can be used by the liver to make glucose

Lactic Acidosis

• Elevated concentrations of lactate in the plasma, often occurring when there is a collapse of the circulatory system or when an individual is in shock
• May occur in myocardial infarction, pulmonary embolism, and uncontrolled hemorrhage