Feeder pathways to glycolysis

Fructose Metabolism - The Sweet Poison

• Pathway Enzymes:

  • Fructokinase: Converts fructose to fructose-1-phosphate (F-1-P).
  • Aldolase B: Cleaves F-1-P into DHAP and glyceraldehyde, which then enter glycolysis.

• Clinical Disorders:

  • Essential Fructosuria: Benign autosomal recessive condition due to Fructokinase deficiency. Fructose appears in blood and urine, but no toxic metabolite accumulates.
  • Hereditary Fructose Intolerance (HFI): Autosomal recessive disorder from Aldolase B deficiency. Symptoms appear after consuming fructose (e.g., in fruits, sucrose).
    • Pathophysiology: Intracellular accumulation of F-1-P (a "phosphate sink"), depleting ATP. This inhibits glycogenolysis and gluconeogenesis.
    • Features: Severe hypoglycemia, vomiting, jaundice, hepatomegaly.

⭐ Aldolase B deficiency leads to intracellular trapping of fructose-1-phosphate, depleting ATP and inorganic phosphate. This inhibits glycogenolysis and gluconeogenesis, causing severe hypoglycemia after fructose ingestion.

📌 Mnemonic: Fructose is to Aldolase B as Galactose is to GALT (FAB-GALT).

Galactose Metabolism - The Milky Menace

• Source: Lactose (milk sugar) is broken down into Glucose + Galactose.
• Pathway: Galactose is phosphorylated by Galactokinase (GALK). Then, Galactose-1-phosphate uridyltransferase (GALT) converts it to Glucose-1-Phosphate, which enters glycolysis.

• Deficiencies & Clinical Features:
  • Classic Galactosemia (GALT deficiency): Most severe. Accumulation of toxic Galactose-1-phosphate and Galactitol. Presents after milk ingestion with jaundice, hepatomegaly, vomiting, and infantile cataracts.
  • Galactokinase (GALK) deficiency: Rare. Causes galactosemia and galactosuria. Galactitol accumulation leads to cataracts.

⭐ The accumulation of galactitol, formed from galactose by aldose reductase in the lens of the eye, is the primary cause of infantile cataracts in galactosemia.

📌 Mnemonic: GALT deficiency is the classic, most severe form. Remember: 'Galactosemia is a GALT-ing, grave condition.'

Mannose & Glycerol - The Side Entrances

• Mannose Pathway

  • Mannose is phosphorylated by Hexokinase to Mannose-6-Phosphate.
  • Phosphomannose isomerase then converts this into Fructose-6-Phosphate, which directly enters glycolysis.

• Glycerol Pathway (Primarily in the liver)

  • Glycerol is phosphorylated by Glycerol kinase to form Glycerol-3-Phosphate.
  • Glycerol-3-phosphate dehydrogenase oxidizes it to Dihydroxyacetone Phosphate (DHAP), a glycolytic intermediate.

⭐ Glycerol, released from the breakdown of triglycerides in adipose tissue, is phosphorylated in the liver by glycerol kinase and then oxidized to dihydroxyacetone phosphate (DHAP), directly entering the glycolytic pathway.

High‑Yield Points - ⚡ Biggest Takeaways

• Fructose is phosphorylated by fructokinase (liver) or hexokinase (muscle) to enter glycolysis.
• Hereditary Fructose Intolerance (Aldolase B deficiency) causes severe hypoglycemia and liver damage upon fructose or sucrose ingestion.
• Essential Fructosuria (fructokinase deficiency) is a benign, asymptomatic condition with fructose in urine.
• Galactose enters glycolysis after conversion to glucose-1-phosphate by the Leloir pathway enzymes.
• Classic Galactosemia (GALT deficiency) causes infantile cataracts, liver failure, and E. coli sepsis.