Alternative glycolytic pathways

Pentose Phosphate Pathway - The Sugar Shuffle

• AKA: Hexose Monophosphate (HMP) Shunt. No ATP is consumed or produced.
• Dual Purpose:
  • NADPH Production: For reductive biosynthesis (e.g., fatty acids, steroids) and protecting against oxidative stress (glutathione reduction).
  • Ribose-5-Phosphate: Precursor for nucleotide synthesis.
• Phases:
  • Oxidative (Irreversible): Rate-limiting enzyme is Glucose-6-phosphate dehydrogenase (G6PD). $G6P + NADP^+ \rightarrow Ribulose-5-P + NADPH$
  • Non-oxidative (Reversible): Interconverts sugars, linking back to glycolysis (Fructose-6-P, GAP).

⭐ G6PD Deficiency: X-linked recessive. ↓NADPH impairs glutathione reduction, leading to hemolytic anemia upon oxidative challenge (e.g., sulfonamides, fava beans). RBCs show Heinz bodies and bite cells.

Fructose Metabolism - Sweet but Sneaky

• Pathway: Primarily in the liver; bypasses the PFK-1 regulatory step of glycolysis.
• Key Enzymes:
  • Fructokinase: Traps fructose in the cell: Fructose → Fructose-1-Phosphate (F1P).
  • Aldolase B: Cleaves F1P → DHAP & Glyceraldehyde, which then enter glycolysis.

• Clinical Correlates:
  • Essential Fructosuria (Fructokinase deficiency): Benign, autosomal recessive condition. Fructose accumulates in urine.
  • Hereditary Fructose Intolerance (Aldolase B deficiency): Severe AR disease. Symptoms (hypoglycemia, vomiting, jaundice) arise after consuming fructose.

⭐ In Aldolase B deficiency, Fructose-1-P accumulation depletes intracellular phosphate ($PO_4^{3-}$), inhibiting both glycogenolysis and gluconeogenesis.

📌 Mnemonic: Fructose issues with Aldolase B are FABulously bad; fructoKinase issues are oKay.

Galactose Metabolism - The Milky Way Path

• Source: Lactose from dairy is hydrolyzed to Galactose + Glucose.
• Function: Converts galactose into glucose-1-phosphate for entry into glycolysis.

• Clinical Syndromes (Autosomal Recessive):
  • GALK Deficiency: Causes accumulation of galactitol.
    • Presents with infantile cataracts. Relatively mild.
  • Classic Galactosemia (GALT Deficiency): Toxic accumulation of Galactose-1-P.
    • Presents in newborns with vomiting, jaundice, hepatomegaly, and failure to thrive.

⭐ A crucial association in classic galactosemia is the markedly increased risk of neonatal E. coli sepsis.

Rapoport-Luebering Shunt - RBC's Oxygen Trick

• An RBC-specific bypass of glycolysis where 1,3-BPG is converted to 2,3-BPG by bisphosphoglycerate mutase.
• This shunt sacrifices the production of 1 ATP molecule.
• Function: 2,3-BPG decreases hemoglobin's affinity for oxygen, promoting O₂ release to peripheral tissues.
• This results in a rightward shift of the oxygen-hemoglobin dissociation curve.

⭐ Levels of 2,3-BPG are elevated in chronic hypoxia (high altitude, COPD) and anemia to improve oxygen delivery.

• The HMP shunt produces NADPH for antioxidant defense and ribose-5-P for nucleotides; it is rate-limited by G6PD.
• The Rapoport-Luebering shunt in RBCs creates 2,3-BPG, which promotes O₂ release from hemoglobin to tissues.
• Fructose metabolism bypasses the key regulatory enzyme PFK-1, allowing rapid, unregulated entry into glycolysis.
• GALT deficiency causes classic galactosemia, leading to toxic accumulation of galactose-1-phosphate and subsequent organ damage.
• The sorbitol pathway contributes to diabetic complications like cataracts and neuropathy via osmotic damage from sorbitol accumulation.