--- module: 088-01 language: en chapter: 88 title: "Carbohydrate Metabolism, Bioenergetics, and Mitochondrial Integration" module_title: "Glycolysis, pyruvate metabolism, gluconeogenesis, and reciprocal glucose control" source_sha256: 4b11458449ea21c70569804baf3a8bfdf8e7a68879a34525bda348ede4c67620 --- # Glycolysis, pyruvate, gluconeogenesis, reciprocal control ## Purpose and glucose entry ### Supplies ATP, intermediates, reducing power, fuel ### Shared reversible reactions, distinct bypass enzymes #### Reciprocal control, not wasteful cycling ### Facilitative or sodium-coupled transporters ### Insulin recruits GLUT4 to muscle and adipose ### Brain uptake largely insulin independent ### Erythrocytes lack mitochondria, depend on glucose ## Trapping and the committed step ### Hexokinase forms glucose six-phosphate #### Charged sugar phosphate cannot diffuse out #### Most hexokinases high affinity, product inhibited ### Hepatic glucokinase low affinity, high capacity #### Not inhibited by glucose six-phosphate #### Sequestration and insulin-dependent expression #### Liver buffers postprandial glucose ### Phosphofructokinase one: committed step #### AMP and fructose 2,6-bisphosphate accelerate #### ATP, citrate, muscle acidity slow ## Energy yield and lactate ### Aldolase and triose-phosphate isomerase #### Both fragments continue as G3P ### G3P dehydrogenase makes NADH ### Phosphoglycerate kinase: first substrate-level ATP ### Pyruvate kinase uses PEP transfer potential ### Net two ATP, two NADH, two pyruvate ### NAD plus regeneration needed to continue #### Lactate dehydrogenase oxidises NADH ### Lactate is shuttled fuel, not waste #### Heart and oxidative muscle consume it #### Rise does not prove tissue hypoxia ## Pyruvate fates and dehydrogenase ### Lactate dehydrogenase and alanine aminotransferase ### Pyruvate carboxylase makes oxaloacetate ### Pyruvate dehydrogenase makes acetyl-CoA irreversibly #### Needs thiamine pyrophosphate, lipoate, CoA, FAD, NAD #### Inhibited by products, kinase, high energy #### Promoted by phosphatase, pyruvate, demand ### Deficiency diverts pyruvate to lactate, alanine #### Brain particularly harmed #### Thiamine deficiency: functional block ### No net glucose from acetyl-CoA ## Gluconeogenic bypasses ### Liver mainly, kidney in prolonged fasting ### Lactate, amino acids, glycerol, propionate #### Even-chain fatty acids give no net carbon ### Pyruvate carboxylase: biotin, CO2, ATP #### Activated by acetyl-CoA #### Oxaloacetate exits as malate or aspartate ### PEP carboxykinase uses GTP #### Decarboxylation drives the reversal ### Fructose-1,6-bisphosphatase bypasses PFK #### Inhibited by AMP, fructose 2,6-bisphosphate ### Glucose-6-phosphatase releases free glucose #### Muscle lacks it, keeps glucose six-phosphate ## Hormonal switching ### Bifunctional enzyme sets fructose 2,6-bisphosphate #### Glucagon, cAMP, PKA lower it #### Glycolysis slows, gluconeogenesis favoured ### Hepatic pyruvate kinase phosphorylated in fasting #### Prevents PEP recycling to pyruvate #### Fructose 1,6-bisphosphate feed-forward activates ### Erythrocyte pyruvate-kinase deficiency #### Low ATP, membrane failure, haemolysis ### Insulin induces glycolytic enzymes in fed state ### Glucagon raises gluconeogenesis in fasting ## Interorgan cycles and substrate supply ### Cori cycle returns lactate to liver ### Glucose-alanine cycle carries carbon and nitrogen #### Nitrogen becomes urea ### Cycles redistribute burden, create no energy ### Fatty-acid oxidation inhibits pyruvate oxidation ### Ethanol NADH diverts pyruvate and oxaloacetate #### Fasting hypoglycaemia with lactic acidosis ## Other sugars and glucose balance ### Fructose enters below phosphofructokinase ### Galactose becomes glucose one-phosphate ### Inherited defects cause toxic accumulation ### Hypoglycaemia from insulin excess or failed output ### Hyperglycaemia: high hepatic output persists ### Renal cortex couples glucose and ammonium ### Disease when one tissue burdens another