(Also called Hexose Monophosphate Shunt / HMP Shunt)
1. Overview
- The PPP is an alternative pathway of glucose oxidation that occurs in the cytosol.
- It does not produce ATP.
- Its primary products are:
- NADPH (reducing power)
- Ribose-5-phosphate (for nucleotide synthesis)
- Intermediates that can re-enter glycolysis.
2. Main Functions
- Production of NADPH for:
- Fatty acid synthesis
- Cholesterol synthesis
- Detoxification of reactive oxygen species (antioxidant defense)
- Production of Ribose-5-phosphate for:
- Synthesis of DNA and RNA (nucleotide biosynthesis)
- Interconversion of sugars to allow flexible metabolic balance between energy production and biosynthesis.
3. Location
- Occurs in the cytosol of cells.
- Especially active in tissues requiring fatty acid synthesis or high antioxidant protection.
4. Organ and Tissue Specificity
PPP is highly active in:
- Liver (fatty acid and cholesterol synthesis)
- Adipose tissue (fat storage and synthesis)
- Lactating mammary glands (lipid synthesis)
- Adrenal cortex (steroid hormone synthesis)
- Testes and ovaries (steroidogenesis)
- Red Blood Cells (RBCs) → for NADPH to protect hemoglobin from oxidative damage
- Rapidly dividing tissues (bone marrow, skin, tumors) → require Ribose-5-phosphate for nucleic acid synthesis
5. Phases of the Pentose Phosphate Pathway
A. Oxidative Phase (Irreversible)
- Glucose-6-phosphate is oxidized to Ribulose-5-phosphate.
- Two molecules of NADPH are produced.
- Key enzyme: Glucose-6-phosphate dehydrogenase (G6PD).
- This step is rate-limiting and highly regulated.
- NADPH inhibits G6PD via feedback control.
B. Non-Oxidative Phase (Reversible)
- Ribulose-5-phosphate is converted into:
- Ribose-5-phosphate (for nucleotide synthesis)
- Or converted into glycolytic intermediates:
- Fructose-6-phosphate
- Glyceraldehyde-3-phosphate
- These intermediates allow metabolic flux to move towards biosynthesis or energy production, depending on the cell's needs.
6. Degradation of Glucose in PPP
- Glucose-6-phosphate enters PPP instead of glycolysis when NADPH is needed.
- After NADPH production, carbon skeletons can return to glycolysis, ensuring no carbon is wasted.
- This gives metabolic flexibility: cells can switch between PPP and glycolysis depending on needs.
7. Anabolic Role of NADPH
- NADPH acts as a reducing agent.
- Used for:
- Fatty acid synthesis
- Cholesterol and steroid hormone synthesis
- Regeneration of reduced glutathione (GSH) in RBCs to neutralize H₂O₂
- Detoxification reactions in the liver via cytochrome P450 system
- Nitric oxide synthesis (NO production) by nitric oxide synthase
Clinical Correlation
- G6PD deficiency → ↓ NADPH → RBCs cannot regenerate reduced glutathione → hemolytic anemia triggered by:
- Infections
- Antimalarial drugs
- Fava beans
8. Anabolic Role of Ribose-5-Phosphate
- Essential for nucleotide synthesis:
- DNA and RNA
- ATP and GTP
- Coenzymes like NAD⁺, NADP⁺, FAD, CoA
- Required for cell division and growth.
- Increased requirement in:
- Bone marrow
- Skin
- Immune cells
- Cancer cells (tumors)