Chapter 22: Generation of Adenosine Triphosphate from Glucose, Fructose, and Galactose: Glycolysis

Glycolysis occurs in the cytoplasm and consists of two distinct phases: an investment phase requiring two ATP molecules catalyzed by hexokinase and phosphofructokinase-1, and a payoff phase generating four ATP and two NADH molecules through substrate-level phosphorylation. Under aerobic conditions, the pyruvate produced from glycolysis enters mitochondria where pyruvate dehydrogenase oxidizes it to acetyl-CoA, feeding into the citric acid cycle to yield approximately thirty to thirty-two ATP per glucose molecule. Conversely, under anaerobic or hypoxic conditions, lactate dehydrogenase reduces pyruvate to lactate to regenerate NAD+, preserving glycolytic function but producing only two ATP per glucose and creating potential for lactic acidosis when lactate accumulates. The chapter details critical regulatory mechanisms controlling phosphofructokinase-1 through allosteric effectors including ATP, AMP, citrate, and fructose 2,6-bisphosphate, as well as regulation of hexokinase and pyruvate kinase. Cytosolic NADH generated during glycolysis must be transferred into mitochondria via the malate-aspartate shuttle or glycerol 3-phosphate shuttle to enable continued ATP production. The Cori cycle mechanism allows lactate produced during anaerobic metabolism to be recycled into glucose in the liver, maintaining blood glucose during exercise or stress. Dietary fructose is metabolized primarily through hepatic pathways involving fructokinase and aldolase B, with genetic defects causing either benign essential fructosuria or the severe hereditary fructose intolerance characterized by hypoglycemia and lactic acidosis. Galactose metabolism begins with phosphorylation by galactokinase followed by conversion through UDP-galactose to glucose 1-phosphate; deficiency in galactose-1-phosphate uridylyltransferase causes classical galactosemia with hepatomegaly, jaundice, cataracts, and cognitive impairment. The chapter integrates clinical case studies demonstrating these principles and describes specialized glycolytic metabolism in tissues including red blood cells, the lens, and tumor cells exhibiting the Warburg effect. Beyond energy production, glycolysis serves biosynthetic functions by providing carbon skeletons for amino acid synthesis, nucleotide synthesis, and fatty acid synthesis, while also generating 2,3-bisphosphoglycerate in red blood cells to regulate hemoglobin oxygen binding affinity.