Overview of Glycolysis

• Glycolysis is a metabolic pathway that converts glucose into pyruvate, generating energy in the form of ATP and NADH.

• It plays a crucial role in cellular respiration and metabolism.

Key Stages of Glycolysis

1. Preparatory Phase

• Purpose: Traps glucose in the cell and prepares it for cleavage.

• Key Steps:

  • Phosphorylation of Glucose: Catalyzed by Hexokinase using ATP. This lowers the intracellular glucose concentration, allowing further uptake.

  • Isomerization: Catalyzed by Phosphoglucose Isomerase to convert glucose-6-phosphate to fructose-6-phosphate.

  • Second Phosphorylation: Catalyzed by Phosphofructokinase-1 (PFK-1), this is the first committed step of glycolysis (adding another phosphate group to fructose-6-phosphate to form fructose-1,6-bisphosphate).

  • Aldolase Action: Cleaves fructose-1,6-bisphosphate into two 3-carbon molecules (GAP and DHAP).

  • Triose Phosphate Isomerase: Converts DHAP to GAP, ensuring a single chemical pathway towards the payoff phase.

2. Payoff Phase

• Purpose: Produces ATP and NADH through the oxidation of GAP to pyruvate.

• Key Steps:

  • Oxidation by Glyceraldehyde-3-phosphate Dehydrogenase: Produces NADH and generates 1,3-Bisphosphoglycerate.

  • First ATP Production: Phosphoglycerate Kinase catalyzes the conversion of 1,3-BPG to 3-Phosphoglycerate, generating ATP via substrate-level phosphorylation.

  • Migration of Phosphate: Phosphoglycerate Mutase rearranges the phosphate for subsequent reactions.

  • Dehydration: Enolase forms phosphoenolpyruvate (PEP) from 2-Phosphoglycerate, preparing for the final ATP-producing step.

  • Second ATP Production: Catalyzed by Pyruvate Kinase, converts PEP to pyruvate while producing a second ATP.

Key Outcomes

• Net production from glycolysis: 2 Pyruvate, 2 NADH, and 2 ATP (from 1 glucose).

Regulation of Glycolysis

• Key Regulating Enzymes:

  • Hexokinase: Inhibited by its product (glucose-6-phosphate).

  • Phosphofructokinase-1 (PFK-1): Highly regulated by energy status (ATP and AMP levels) and fructose-2,6-bisphosphate.

  • Pyruvate Kinase: Regulated by ATP (inhibition) and fructose-1,6-bisphosphate (activation).

Glycolysis vs. Gluconeogenesis

• Locations: Glycolysis mainly in muscle and brain; gluconeogenesis primarily in the liver and kidney cortex.

• Energy Requirement: Glycolysis produces ATP; gluconeogenesis requires ATP (4 ATP, 2 GTP, and 2 NADH per glucose).

• Reciprocal Regulation: Glycolysis is activated when ATP is needed; gluconeogenesis is favored when glucose is scarce.

Anaerobic Glycolysis

• Occurs when oxygen is limited, leading to the production of lactate in muscle cells and certain other tissues (like erythrocytes).

• Efficient under conditions where energy demand is high, but oxygen supply is low.

Hormonal Regulation

• Insulin and Glucagon: Insulin stimulates glycolysis while glucagon promotes gluconeogenesis. This balance helps maintain blood glucose levels during different metabolic states.

Clinical Relevance

• Understanding glycolysis is fundamental in fields like biochemistry, medicine, and physiology, particularly concerning metabolic diseases and cancer metabolism (Warburg effect).

• Abnormalities in glycolysis regulation can lead to conditions such as lactic acidosis.