OIA1003 GLYCOLYSIS

Glycolysis

A 10-step cytoplasmic pathway that breaks down glucose into pyruvate, generating ATP and NADH.

Location of glycolysis

Occurs in the cytoplasm of all mammalian cells.

Glycolysis under aerobic conditions

Pyruvate enters mitochondria, converted to acetyl-CoA, enters TCA cycle.

Glycolysis under anaerobic conditions

Pyruvate is reduced to lactate by lactate dehydrogenase, regenerating NAD⁺.

Tissues relying on anaerobic glycolysis

Red blood cells, exercising muscles, poorly oxygenated tissues (e.g., retina, skin).

Clinical importance of glycolysis

Essential for energy in ischemic tissue and RBCs; provides intermediates for lipogenesis and amino acid synthesis.

GLUT transporters

Family of facilitated diffusion proteins (GLUT-1 to GLUT-14); GLUT-4 is insulin-dependent in muscle/adipose tissue.

SGLT (sodium-glucose cotransporter)

Active transporter that moves glucose against its gradient, especially in intestines and renal tubules.

Energy investment phase

Steps 1–5: Use 2 ATP to phosphorylate glucose and prepare it for cleavage.

Energy generation phase

Steps 6–10: Yield 4 ATP and 2 NADH per glucose, resulting in a net gain of 2 ATP.

Hexokinase/Glucokinase

Catalyze phosphorylation of glucose to glucose-6-phosphate; irreversible; inhibited by G6P.

Phosphoglucose isomerase

Converts glucose-6-phosphate to fructose-6-phosphate; reversible.

Phosphofructokinase-1 (PFK-1)

Converts fructose-6-phosphate to fructose-1,6-bisphosphate; rate-limiting and committed step.

Aldolase

Cleaves F1,6BP to DHAP and glyceraldehyde-3-phosphate (G3P); reversible.

Triose phosphate isomerase

Converts DHAP to G3P to ensure both products proceed through glycolysis.

Glyceraldehyde-3-phosphate dehydrogenase (GAPDH)

Converts G3P to 1,3-BPG; generates NADH.

Phosphoglycerate kinase

Converts 1,3-BPG to 3-PG; generates ATP via substrate-level phosphorylation.

Phosphoglycerate mutase

Shifts phosphate from C3 to C2; prepares for dehydration.

Enolase

Removes water from 2-PG to form phosphoenolpyruvate (PEP).

Pyruvate kinase

Converts PEP to pyruvate; irreversible; produces ATP.

Aerobic fate of pyruvate

Oxidative decarboxylation to acetyl-CoA in mitochondria by pyruvate dehydrogenase.

Anaerobic fate of pyruvate

Reduced to lactate by lactate dehydrogenase; regenerates NAD⁺.

Carboxylation to oxaloacetate

Pyruvate carboxylase converts pyruvate to OAA for gluconeogenesis or TCA replenishment.

Key regulatory enzymes

Hexokinase/glucokinase, PFK-1, and pyruvate kinase—each catalyzes irreversible steps.

PFK-1 regulation

Inhibited by ATP and citrate; activated by AMP and fructose 2,6-bisphosphate.

PFK-2 role

Bifunctional enzyme that synthesizes or degrades F2,6BP; influenced by insulin and glucagon.

Pyruvate kinase regulation

Activated by F1,6BP (feed-forward); inactivated by phosphorylation via cAMP when glucagon is high.

Hexokinase vs Glucokinase

Hexokinase inhibited by G6P; glucokinase active at higher glucose concentrations and induced by insulin.

Insulin effect

Stimulates glycolysis by inducing GK, PFK-1, and PK expression and activation.

Glucagon effect

Suppresses glycolysis in liver by inactivating GK, PFK-1, and PK through phosphorylation.

Well-fed state

↓ Glucagon, ↑ Insulin → ↑ Glycolysis.

Starved state

↑ Glucagon, ↓ Insulin → ↓ Glycolysis, ↑ Gluconeogenesis.

ATP yield in anaerobic glycolysis

Net gain of 2 ATP per glucose (2 used, 4 produced); no NADH gain.

ATP yield in aerobic glycolysis

Net gain of 5 ATP: 2 from substrate-level phosphorylation, ~3 from oxidation of 2 NADH.

Lactic acidosis

Excess lactate production due to hypoxia or mitochondrial dysfunction causes acid-base imbalance.

Exercise and glycolysis

During intense activity, anaerobic glycolysis predominates → lactate builds up → muscle cramps.

RBC metabolism

RBCs rely entirely on anaerobic glycolysis for ATP, as they lack mitochondria.

Cancer metabolism

Tumor cells favor aerobic glycolysis (“Warburg effect”) to support rapid growth.

Inherited glycolytic enzyme deficiencies

E.g., pyruvate kinase deficiency causes hemolytic anemia due to low ATP in RBCs.

Glycolysis in biosynthesis

Provides precursors for amino acids, lipids (via G3P), and nucleotides.