HMP Shunt Overview and Functions

HMP Shunt (Hexose Monophosphate Shunt)

• Definition: An alternative pathway of glucose oxidation where ATP is neither produced nor used.
• Location: Cytoplasm of many tissues.
• Phases: Occurs in two phases.
  • Oxidative (irreversible): 3 glucose molecules are converted to 3 ribulose-5-P, producing NADPH+H+ and CO2.
  • Non-oxidative (reversible): 3 ribulose-5-P are converted to 2 glucose-6-P and 1 glyceraldehyde-3-P.

Functions of HMP Shunt

• Production of pentoses (ribose-5-P): crucial for DNA, RNA, NAD, FAD, ATP, and GTP synthesis.
• Production of NADPH+H+: Essential for fatty acid and steroid hormone synthesis, non-essential amino acid synthesis, converting pyruvate to malate via malic enzyme, and reduced glutathione synthesis in erythrocytes.

Glutathione Reductase and Reduced Glutathione

• Reduced glutathione is needed for cellular hydrogen peroxide removal (maintaining cell membrane integrity in RBCs).
• The enzyme glutathione peroxidase converts hydrogen peroxide to water, while the enzyme glutathione reductase regenerates reduced glutathione.

Regulation of HMP Shunt

• Glucose-6-phosphate dehydrogenase (G6PD) is the key enzyme.
• Stimulated by insulin and NADP+.
• Inhibited by NADPH+H+ and acetyl CoA.

Uronic Acid Pathway

• Definition: An alternative pathway for glucose oxidation producing glucuronic acid.
  • Location: Cytoplasm of many tissues.
• Importance:
  • Production of UDP-glucuronic acid, a precursor for
  • Synthesis of glycosaminoglycans (GAGs).
  • Synthesis of vitamin C (L-ascorbic acid) in animals (not humans – humans lack L-gluconolactone oxidase)
  • Conjugation reactions: Making substances like bilirubin more water-soluble for excretion.
  • Detoxification reactions: Making toxic compounds less toxic.
  • Production of pentoses (ribose-5-P).

Glycogen Metabolism

• Definition: Glycogen is the storage form of carbohydrates in animals, composed of α-D glucose units linked by α1-4 glucosidic bonds and α1-6 glucosidic bonds at branch points.
• Storage Location: Liver and muscles.

Liver Glycogen

• Percentage: Up to 6% of liver mass.
• Function: Maintaining blood glucose levels during fasting.
• Depletion: Depletes after 12-18 hours of fasting.
• Regulation: Glucagon stimulates glycogenolysis (breakdown).

Muscle Glycogen

• Percentage: Rarely exceeds 1% of muscle mass.
• Function: Acts as a glucose-6-P source for muscle glycolysis.
• Depletion: Depletes after prolonged vigorous exercise.
• Regulation: No effect from glucagon.

Glycogenesis

• Definition: Synthesis of glycogen from glucose.
• Location: Cytoplasm of liver and muscle cells.
• Sources for liver glycogen:
  • Blood glucose
  • Other hexoses (galactose and fructose)
  • Non-carbohydrate sources (e.g., lactate and glycerol via gluconeogenesis).
• Sources for muscle glycogen: Blood glucose only.
• Steps: Several enzymatic steps, including formation of UDP-glucose, the use of a glycogen primer (often a protein glycogenin), and elongation to 11 glucose units using glycogen synthase; lastly branching by branching enzyme.

Glycogenolysis

• Definition: Breakdown of glycogen into glucose or glucose-6-P.
• Location: Cytoplasm of liver and muscle cells.
• Steps:
  • Phosphorylase enzyme: Breaks down α1-4 glycosidic bonds by phosphorylysis (adding phosphate).
  • Debranching enzyme: Removes α1-6 branch points.
  • Glucan transferase enzyme: transfers three glucose residues to adjacent chain to shorten branch point, leaving one glucose attached at α1-6 branch point.

Fate of Glucose-6-Phosphate

• Liver: Contains glucose-6-phosphatase for converting glucose-6-phosphate to glucose for release into the blood.
• Muscle: Lacks glucose-6-phosphatase, so glucose-6-phosphate remains in the muscle during glycogenolysis.

Regulation of Glycogenesis and Glycogenolysis

• Coordinated regulation: Conditions stimulating one process inhibit the other.
• Key enzymes:
  • Glycogen synthase: Active (dephosphorylated) form vs. inactive (phosphorylated) form.
  • Phosphorylase: Active (phosphorylated) form vs. inactive (dephosphorylated) form.

Regulation During Fasting

• Blood glucose decrease stimulates epinephrine release in muscles and glucagon in the liver.
• These hormones activate adenylate cyclase, producing cAMP.
• cAMP activates protein kinase which phosphorylates and inactivates glycogen synthase, and phosphorylates and activates phosphorylase, inhibiting glycogen synthesis and activating glycogenolysis.

Regulation After Meals

• Increased blood glucose stimulates insulin release.
• Insulin stimulates glycogen synthesis.
• Insulin inhibits glycogen breakdown.
• This process occurs via phosphodiesterase, breaking down cAMP to 5AMP, halting glycogen degradation and stimulating phosphatase activity which removes phosphate groups from enzymes for deactivation.

Explore the Hexose Monophosphate Shunt (HMP Shunt), an alternative glucose oxidation pathway. Understand its phases, the production of vital biomolecules, and the role of reduced glutathione in cellular health. This quiz covers the biochemical processes and their significance in various tissues.