02: Carbohydrate Metabolism: Glycolysis and Gluconeogenesis - Study Notes

Carbohydrate Metabolism Overview

Focus on Glycolysis and Gluconeogenesis.

Presented by Dr. Anand Sridhar, Medical Biochemistry II.

Section Objectives

Stages of carbohydrate digestion in the GI tract.

Glucose transport mechanisms and glucose transporters (GLUT).

Definition and process of glycolysis.

Enzymes, reactants, products, and reaction types involved in glycolysis.

Energetics and hormonal regulation of glycolysis.

Fermentation processes and chemical fates of pyruvate.

Carbohydrate Digestion

Salivary Amylase:

• Cleaves α-(1,4)- glycosidic bonds; inactivated by stomach acid.
• Pancreatic secretions neutralize stomach acid, leading to the breakdown of oligosaccharides to monosaccharides.
• Monosaccharides enter portal circulation; glucose stored as glycogen in the liver.

Glucose

A hexose monosaccharide and major carbohydrate form absorbed by the body.

Essential energy source for the brain (20% oxygen consumption, 25% glucose utilization).

Uptake into cells via glucose transporters (GLUT).

Glucose Transport

Cannot diffuse directly into cells; requires transport mechanisms.

Facilitated Diffusion:

• Na+-independent and Na+-dependent transport includes two GLUT types:
• Na+-independent: GLUT family.
• Na+-dependent: SGLT (Sodium-dependent glucose transporters).

GLUT Transporters

GLUT1: Most tissues; basal glucose uptake.

GLUT2: Liver, kidneys, pancreas; insulin-sensitive.

GLUT3: Brain; low-level glucose transport.

GLUT4: Muscle and adipose; translocates in response to insulin.

GLUT5: Small intestine; fructose transporter.

Glycolysis

Main metabolic pathway for glucose breakdown, occurs in the cytosol of all cells.

Process summary:

• 1 glucose (6 carbons) → 2 pyruvate (3 carbons) + energy.
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Investment Phase: Steps

1. Hexokinase: Glucose → Glucose 6-phosphate (ATP investment).
2. Phosphoglucose Isomerase: Converts Glucose 6-P to Fructose 6-P.
3. Phosphofructokinase-1 (PFK-1): Fructose 6-P → Fructose 1,6-bisphosphate (regulated and irreversible).
4. Aldolase: Cleavage of Fructose 1,6-P to glyceraldehyde 3-phosphate (G3P) and dihydroxyacetone phosphate (DHAP).
5. Triose Phosphate Isomerase: Interconversion of DHAP and G3P, leading to G3P accumulation.
6. Dehydrogenase Reaction: G3P to 1,3-bisphosphoglycerate (NAD+ to NADH).
7. Phosphoglycerate Kinase: Forms ATP from ADP (substrate level phosphorylation).
8. Mutase: 3-phosphoglycerate → 2-phosphoglycerate (isomerization).
9. Enolase: 2-phosphoglycerate → phosphoenolpyruvate (PEP).

Energetics of Glycolysis

Investment Phase: 2 ATP used.

Payoff Phase: 4 ATP produced and 2 NADH; net gain = 2 ATP.

Hormonal Regulation of Glycolysis

Insulin promotes glycolysis; glucagon inhibits it.

Activation of key enzymes when nutrient-rich (carb-rich diet).

Lactate Fermentation

In absence of oxygen, pyruvate reduced to lactate (Cori Cycle).

Important for regenerating NAD+, allowing glycolysis to continue in anaerobic conditions.

Alternate fates of Pyruvate

Acetyl CoA formation for TCA cycle.

Carboxylation to oxaloacetate for gluconeogenesis.

Reduction to ethanol in fermentation processes.

Gluconeogenesis

Synthesis of glucose from non-carbohydrate sources: pyruvate, lactate, etc.

Mostly occurs in the liver; key aerobic process.

Begins with pyruvate → oxaloacetate → phosphoenolpyruvate through several key enzymatic steps.

Key steps and enzymes:

• Pyruvate Carboxylase marks starting point in mitochondria.
• Fructose 1,6-bisphosphatase regulates steps opposing those of glycolysis.
• Glucose 6-phosphatase finalizes gluconeogenesis.

Cori Cycle

Lactate from muscle can be recycled into glucose in the liver, maintaining glucose supply during fasting or intense exercise.