Carbohydrate Metabolism

🔄 Overview: Major Pathways of Carbohydrate Metabolism

Carbohydrate metabolism involves a network of interconnected pathways:

1. Glycolysis

2. Gluconeogenesis

3. Glycogenesis

4. Glycogenolysis

5. Hexose Monophosphate (HMP) Shunt

6. Uronic Acid Pathway

7. Pyruvate Metabolism

8. TCA Cycle & Oxidative Phosphorylation

9. Other metabolic pathways include: (Fructose/Galactose/Lactose/Cori/BPG)

Carbohydrates, primarily glucose, serve as:

✅The main energy source for all tissues

✅The sole fuel for RBCs, the brain (under normal conditions), and the renal medulla

✅A precursor for amino acids, nucleotides, and fatty acids

⚕️As a medical student, understanding carbohydrate metabolism helps decode:

✅Diabetes mellitus, hypoglycemia, lactic acidosis

✅Glycogen storage diseases

✅Clinical tests like HbA1c, GTT, C-peptide, and RBS

🌱Why Carbohydrate Metabolism Matters in Medicine

✍️ Quick Notes for Medical Understanding:

• Catabolic: Breaks molecules to release energy (e.g., glycolysis, glycogenolysis).

• Anabolic: Builds complex molecules using energy (e.g., gluconeogenesis, glycogenesis).

• Amphibolic: Functions in both anabolism and catabolism (e.g., TCA cycle).

• HMP Shunt provides reducing power (NADPH) for anabolic reactions & ribose sugars for nucleotide synthesis.

• The Uronic acid pathway helps in detoxification by forming conjugates with bilirubin, drugs, etc.

⚡ 1. Glycolysis – The Central Energy Pathway

🔬 Location: Cytoplasm of all cells

🧪 End-product: Pyruvate (aerobic) or Lactate (anaerobic)

🔄 Net Reaction:

Glucose + 2 ADP + 2 Pi + 2 NAD⁺ → 2 Pyruvate + 2 ATP + 2 NADH + 2 H⁺

Key Regulatory Enzymes:

• Hexokinase / Glucokinase (liver-specific)

• Phosphofructokinase-1 (PFK-1) – Rate-limiting step

• Pyruvate kinase

🩺 Clinical Relevance:

• Pyruvate kinase deficiency → Hemolytic anemia

• Cancer cells show increased glycolysis (Warburg effect)

• Lactic acidosis occurs during hypoxia/sepsis due to anaerobic glycolysis

Introduction to Glycolysis

• Definition: Glycolysis is the metabolic pathway that converts glucose into pyruvate, producing ATP and NADH.

• Location: Cytoplasm of all cells.

• Importance: First step in glucose catabolism.

🧭Glycolysis Pathway Steps (I)

1. Energy Investment Phase (Steps 1–5):

• Glucose phosphorylation → Fructose-1,6-bisphosphate formation.

• Enzymes: Hexokinase, Phosphofructokinase-1 (PFK-1).

• ATP consumed: 2 molecules.

🧠 Note: Now, 2 molecules of G3P proceed through the remaining steps.

🧭Glycolysis Pathway Steps (II)

2. Energy Payoff Phase (Steps 6–10):

• Glyceraldehyde-3-phosphate oxidation → Pyruvate formation.

• Enzymes: Glyceraldehyde-3-phosphate dehydrogenase, Pyruvate kinase.

• ATP produced: 4 molecules.

• NADH produced: 2 molecules.

🌿 2. Gluconeogenesis – Glucose from Non-Carbs

🔁 Bypass Enzymes:

• Pyruvate carboxylase

• PEP carboxykinase

• Fructose-1,6-bisphosphatase

• Glucose-6-phosphatase

🔬 Location: Liver (mostly), kidney (partially)

🌱 Precursors: Lactate, alanine, glycerol

🩺 Clinical Relevance:

• Essential during fasting, stress, and starvation

• Defects → hypoglycemia, lactic acidosis, hyperuricemia

• Von Gierke’s disease: Deficiency of G6Pase → hepatomegaly, fasting hypoglycemia

🌿 3. Glycogenesis – Storage of Glucose

🔬 Location: Liver and muscle

🔑 Key Enzyme: Glycogen synthase

🔁 Steps: Glucose → G6P → G1P → UDP-glucose → Glycogen

🩺 Clinical Relevance:

• Regulated by insulin (activates) and glucagon (inhibits)

• Deficiency → Andersen’s disease (branching enzyme defect)

⚡ 4. Glycogenolysis – Releasing Stored Glucose

🩺 Clinical Relevance:

• McArdle disease: Muscle phosphorylase deficiency → exercise intolerance

• Hers disease: Liver phosphorylase deficiency → hepatomegaly, hypoglycemia

🔬 Location: Liver (to maintain blood glucose), muscle (for local use)

🔑 Key Enzyme: Glycogen phosphorylase

🔁 Steps: Glycogen → G1P → G6P → Glucose (only in liver)

🌿 5. HMP Shunt (Pentose Phosphate Pathway)

🔬 Location: Cytoplasm (esp. in liver, RBCs, adrenal cortex)

🌟 Functions:

• Produces NADPH (for reductive biosynthesis & GSH regeneration)

• Generates ribose-5-phosphate (for nucleotide synthesis)

🔑 Key Enzyme: G6PD (Glucose-6-phosphate dehydrogenase)

🩺 Clinical Relevance:

• G6PD deficiency → hemolysis under oxidative stress (fava beans, infections, sulfa drugs)

🔁 6. Uronic Acid Pathway

(Glucuronic Acid Pathway)

📍 Location

Primarily in the liver

Also occurs in the kidneys and the intestinal mucosa

Cellular location: Cytosol

🔁 Type of Pathway

✅ Anabolic Pathway

• It does not generate ATP directly.

• It uses glucose derivatives to produce glucuronic acid and other biosynthetic precursors.

• Mainly supports biosynthesis, detoxification, and conjugation.

You didn’t come this far to stop

You didn’t come this far to stop

🔥 7. Pyruvate Metabolism

🩺 Clinical Relevance:

Pyruvate dehydrogenase deficiency → lactic acidosis, neurological defects

Cori cycle: Lactate from muscles → liver → glucose

🔄 TCA Cycle (Citric Acid Cycle / Krebs Cycle)

📍 Location

Mitochondrial Matrix (in all aerobic cells except mature RBCs, which lack mitochondria)

⚙️ Nature of the Pathway

✅ Amphibolic

Catabolic: Oxidizes Acetyl-CoA to CO₂ → produces NADH, FADH₂, and GTP (used for ATP generation).

Anabolic: Intermediates serve as precursors for biosynthesis (e.g., amino acids, heme, gluconeogenesis).

⚡ Oxidative Phosphorylation

(Electron Transport Chain)

📍 Location: Inner Mitochondrial Membrane

⚙️ Type of Pathway

✅ Strictly Catabolic

Produces >90% of cellular ATP in aerobic cells.

Oxygen is the final electron acceptor → forms water.

🔁 Process Summary

• Electrons from NADH & FADH₂ pass through Complexes I–IV, releasing energy.

• This energy pumps H⁺ ions into the intermembrane space, creating a proton gradient.

• ATP synthase (Complex V) uses this gradient to produce ATP from ADP + Pi.

🔬 Biological Significance

• Converts chemical energy from nutrients into ATP, the universal energy currency.

• Essential for cell survival, especially in high-energy organs (brain, heart, muscle).

• Also generates heat in brown adipose tissue (non-shivering thermogenesis via uncoupling proteins).

⚕️ Clinical Significance