Biochemistry Lecture 19: Glycolysis

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Study Notes

Specific Objectives: Students will understand the glycolytic pathway of glucose and its hormonal regulation.

Glucose cannot directly diffuse into cells.
Two transport mechanisms exist:
- Na+-independent facilitated diffusion transport
- Na+-monosaccharide co-transporter system (SGLT)

Mediated by a family of 14 glucose transporters in cell membranes.
Examples:
- GLUT-1: Abundant in erythrocytes and blood-brain barrier, but low in adult muscle.
- GLUT-2: The transporter in liver cells.
- GLUT-3: The primary glucose transporter in neurons.
- GLUT-4: Abundant in adipose tissue and skeletal muscle. Insulin stimulates GLUT-4.

The glycolytic pathway occurs in the cytoplasm of cells in all body tissues.
It breaks down glucose to produce energy (ATP) and intermediates for other metabolic pathways.
Two types of glycolysis:
- Aerobic glycolysis: Breaks down glucose with enough oxygen and mitochondria. Pyruvate is the end product.
- Anaerobic glycolysis: Glucose is converted to lactate without oxygen. This allows ATP production in tissues lacking mitochondria or those deprived of oxygen (e.g., RBCs).

Anaerobic glycolysis: Two ATP are generated for each molecule of glucose converted to two molecules of lactate. There is no net production or consumption of NADH.
Aerobic glycolysis: The direct consumption and formation of ATP is the same as in anaerobic glycolysis. Two molecules of NADH are also produced per molecule of glucose. NADH produces approximately three ATP in the electron transport chain per molecule. The net energy released is 8 ATP.

Glucagon: Secreted in hypoglycemia or carbohydrate deficiency. Inhibits key glycolytic enzymes (glucokinase, phosphofructokinase-1, pyruvate kinase).
Insulin: Secreted in hyperglycemia and after carbohydrate feeding. Stimulates glycolytic key enzymes.

Hexokinase:
- In most tissues, catalyzes glucose phosphorylation.
- Low Km, high affinity for glucose. Efficient phosphorylation even at low glucose concentrations.
- Low Vmax, cannot phosphorylate more sugars than the cell can use.
Glucokinase:
- Predominant enzyme in liver parenchymal cells and β cells of the pancreas (also called hexokinase D or type IV).
- Functions as a glucose sensor in β cells, determining the threshold for insulin secretion.
- Facilitates glucose phosphorylation in the liver during hyperglycemia.
- High Km, requires higher glucose concentration.
- High Vmax, effectively removes glucose delivered by the portal blood.
PFK-1 (Phosphofructokinase-1):
- The most important control point in glycolysis.
- Inhibited allosterically by elevated levels of ATP and citrate.
- Activated by high AMP concentrations (indicating low energy stores).

Catalyzes the conversion of phosphoenolpyruvate (PEP) to pyruvate, forming ATP.
Deficiency leads to hemolytic anemia due to the lack of ATP in red blood cells, which are essential for maintaining their shape and function. ATP is required to fuel pumps for maintaining the biconcave shape.

Anemia results from the reduced rate of glycolysis and decreased ATP production.
Red blood cell membrane alterations, leading to phagocytosis by macrophages in the spleen.
Premature death and lysis of red blood cells cause hemolytic anemia.

Champe, P. C., Harvey, R. A., & Ferrier, D. R. (2005). Biochemistry (5th or 6th Edition). Lippincott's Illustrated Reviews.
Vasudevan, D. M., Sreekumari, S., & Kannan, V. (2011). Textbook of Biochemistry for Medical Students (6th Edition).