5. HMP SHUNT

HMP Shunt (Pentose Phosphate Pathway)

The HMP shunt, also known as the pentose phosphate pathway or hexose monophosphate shunt, is an alternative glucose oxidation pathway occurring in the cytosol. This anabolic pathway is crucial for generating reducing power in the form of NADPH and pentose sugars required for nucleotide synthesis.

Pathway Overview:

  • Involves an oxidative phase converting glucose-6-phosphate into ribulose-5-phosphate with production of NADPH.
  • A non-oxidative phase interconverts sugar phosphates to generate ribose-5-phosphate and glycolytic intermediates.
  • Operates in tissues including liver, adipose, RBCs, adrenal cortex, and lactating mammary glands.
  • Functions adaptively to cellular needs for NADPH or ribose sugars.

Oxidative Phase:

  1. Glucose-6-phosphate dehydrogenase (G6PD): Catalyzes oxidation of glucose-6-phosphate generating NADPH and producing 6-phosphogluconolactone. Requires Mg2+ or Ca2+.
  2. Lactonase: Hydrolyzes 6-phosphogluconolactone to 6-phosphogluconate, metal ion-dependent.
  3. 6-phosphogluconate dehydrogenase: Oxidizes and decarboxylates 6-phosphogluconate to ribulose-5-phosphate, producing NADPH and CO2.

Non-Oxidative Phase:

  • Phosphopentose isomerase: Converts ribulose-5-phosphate to ribose-5-phosphate.
  • Phosphopentose epimerase: Converts ribulose-5-phosphate to xylulose-5-phosphate.
  • Transketolase: Transfers two-carbon units between sugar phosphates to generate sedoheptulose-7-phosphate and glyceraldehyde-3-phosphate. Requires thiamine pyrophosphate (TPP) and Mg2+.
  • Transaldolase: Transfers three-carbon units to produce erythrose-4-phosphate and fructose-6-phosphate.
  • Further transketolase reactions regenerate glycolytic intermediates fructose-6-phosphate and glyceraldehyde-3-phosphate.

Biological Importance:

  • NADPH acts as reducing agent in fatty acid, cholesterol, bile acid, hormone synthesis, and in detoxification processes.
  • Ribose-5-phosphate serves as precursor for nucleotide and nucleic acid biosynthesis.
  • In RBCs, NADPH maintains glutathione in reduced state to protect against oxidative damage.
  • NADPH is essential for respiratory burst in neutrophils for microbial killing.
  • Intermediates link with glycolysis and metabolic flexibility.

Medical Importance:

  • Glucose-6-phosphate dehydrogenase deficiency: Genetic defect leading to reduced NADPH, causing increased vulnerability of RBCs to oxidative damage and hemolytic anemia under stress.
  • Transketolase deficiency: Seen in thiamine deficiency, linked to neurological disorders like Wernicke-Korsakoff.

Regulation:

The pathway flux depends on cellular NADPH demand. G6PD is the rate-limiting enzyme, activated by NADP+ availability and inhibited by NADPH. When pentoses are needed more than NADPH, intermediates enter glycolysis bypassing NADPH production. Hormones like insulin indirectly regulate HMP via glucose availability.

The HMP shunt thus balances cellular anabolic needs and oxidative stress protection, representing a vital metabolic pathway in health and disease.

Detailed Notes:
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