HMP Shunt & Other Pathways
The Hexose Monophosphate (HMP) Shunt, also called the Pentose Phosphate Pathway (PPP), is an alternative pathway for glucose-6-phosphate oxidation. It does NOT produce ATP directly but generates two essential products: NADPH and Ribose-5-phosphate.
Location & Tissues
Cytosol. Most active in tissues with high biosynthetic activity: Liver (FA synthesis), Adipose tissue, Adrenal cortex (steroid synthesis), RBCs (antioxidant defense), Mammary gland, and Gonads (steroidogenesis).
Two Phases
Oxidative Phase (irreversible):
- G6P → 6-Phosphogluconolactone + NADPH [G6PD — rate-limiting, NADP+ activates]
- 6-Phosphogluconolactone → 6-Phosphogluconate [Lactonase]
- 6-Phosphogluconate → Ribulose-5-P + CO₂ + NADPH [6-Phosphogluconate dehydrogenase]
Net: 1 G6P + 2 NADP+ → 1 Ribulose-5-P + 2 NADPH + CO₂
Non-oxidative Phase (reversible — Transketolase and Transaldolase reactions): Interconverts pentose phosphates with glycolytic intermediates (F6P, G3P). Allows return to glycolysis if ribose-5-P is not needed.
NADPH Functions
- Reductive biosynthesis: Fatty acid synthesis, Cholesterol synthesis, Steroid hormone synthesis
- Antioxidant defense: Maintains Glutathione in reduced form (GSH) via Glutathione reductase
- Phagocyte NADPH oxidase: Produces superoxide (O₂•⁻) to kill bacteria (Respiratory burst)
- Cytochrome P450 reactions (drug metabolism)
- Nitric oxide synthase (NO production)
G6PD Deficiency
Most common enzyme deficiency worldwide (X-linked recessive; more common in African, Mediterranean, Asian populations). RBCs cannot maintain GSH → oxidative stress → Heinz bodies form → hemolysis.
Triggered by: Primaquine (antimalarial), Dapsone, Fava beans, infections, naphthalene (moth balls). Presents as: episodic hemolytic anemia, jaundice.
Fructose Metabolism
- In Liver: Fructose → Fructose-1-P [Fructokinase] → DHAP + Glyceraldehyde [Aldolase B] → enters glycolysis
- Bypasses PFK-1 regulation → unregulated entry into glycolysis → FA synthesis, lactic acidosis
- Essential Fructosuria: Fructokinase deficiency; benign
- Hereditary Fructose Intolerance: Aldolase B deficiency; F1P accumulates → liver damage, hypoglycemia (severe; avoid fructose and sucrose)
Galactose Metabolism
Galactose → Galactose-1-P [Galactokinase] → UDP-Galactose [GALT enzyme] → UDP-Glucose [Epimerase]. Used for lactose synthesis in mammary gland and glycoprotein/glycolipid synthesis.
Classic Galactosemia: GALT deficiency → Gal-1-P accumulates; also galactitol (via aldose reductase) → cataracts; liver cirrhosis; intellectual disability; E. coli sepsis in neonates.