HMP Shunt Overview

HMP Shunt (Hexose Monophosphate Shunt)

• Definition: An alternative pathway for glucose oxidation where ATP is neither produced nor used.
• Location: Occurs in the cytoplasm of many tissues.
• Phases: The process occurs in two phases: oxidative (irreversible) and non-oxidative (reversible).
• Oxidative Phase: Three glucose molecules convert to three ribulose-5-phosphates, producing NADPH+H+ and CO2.
• Non-Oxidative Phase: Three ribulose-5-phosphates convert to two glucose-6-phosphates and one glyceraldehyde-3-phosphate. These reactions are reversible.
• Functions: Important for pentose (ribose-5-phosphate) synthesis (e.g., DNA, RNA), NADPH+H+, synthesis of fatty acids, steroid hormones, and non-essential amino acids. Additionally, NADPH+H+ is crucial for glutathione reduction, crucial to protect erythrocytes from oxidative damage
• Regulation: Glucose-6-phosphate dehydrogenase is the key enzyme. It's stimulated by insulin and NADP+, inhibited by NADPH+H+ and acetyl-CoA.

Uronic Acid Pathway

• Definition: An alternative pathway for glucose oxidation, converting glucose into glucuronic acid.
• Location: Occurs in the cytoplasm of many tissues.
• Importance: Produces UDP-glucuronic acid, a key substrate for various functions.
• Synthesis of Substrates:
  • Glycosaminoglycans (GAGs)
  • Vitamin C (ascorbic acid) in other animals, not humans (humans lack L-gluconolactone oxidase).
• Conjugation Reactions: Makes substances like bilirubin more water-soluble for excretion.
• Detoxification Reactions: Modifies toxic compounds to make them less toxic.
• Production of Pentose: The pathway also produces pentoses.

Glycogen Metabolism

• Glycogen: The storage form of carbohydrates in animals.
• Structure: Formed of α-D glucose units linked by α1-4 glucosidic bonds and α1-6 bonds at branch points.
• Storage Location: Primarily stored in the liver and muscles.

Liver Glycogen

• Function: Maintains blood glucose levels during fasting.
• Concentration: Usually up to 6% of liver mass.
• Depletion: Empties after approximately 12-18 hours of fasting.
• Regulation: Glucagon stimulates glycogenolysis (break down) in liver cells.

Muscle Glycogen

• Function: Acts as a quick source of glucose-6-phosphate for muscle glycolysis.
• Concentration: Generally less than 1% of muscle mass.
• Depletion: Empties during prolonged or vigorous exercise.
• Regulation: Glucagon has no impact on muscle glycogen.

Glycogenesis

• Definition: The synthesis of glycogen from glucose.
• Location: Occurs in the cytoplasm of liver and muscle cells.
• Sources of Glucose Units:
  • Blood glucose
  • Other hexoses (e.g., galactose, fructose)
  • Non-carbohydrate sources generated by gluconeogenesis (e.g., lactate, glycerol)
• For Muscle Glycogen: Blood glucose is the sole source for muscle glycogen synthesis.

Glycogenolysis

• Definition: The breakdown of glycogen into glucose.

• Location: Cytoplasm of liver and muscle cells.

• Steps:

  • Phosphorylase Enzyme: The key enzyme, breaks down α1-4 glycosidic bonds, producing glucose-1-phosphate.
  • Glucan Transferase Enzyme: Moves 3 glucose units from one branch to another, leaving a single glucose unit on a 1-6 branch.
  • Debranching Enzyme: Removes the single glucose unit on the 1-6 branch. Note: Glucose-1-P is then converted to glucose-6-phosphate.

• Fate of Glucose-6-Phosphate:

  • Liver: Contains glucose-6-phosphatase, converts G-6-P into free glucose released into the bloodstream.
  • Muscle: Doesn't contain glucose-6-phosphatase, G-6-P remains within muscle cells, used for muscle metabolism.

Regulation of Glycogenesis and Glycogenolysis

• Coordinated Regulation: Glycogenesis and glycogenolysis are regulated reciprocally; stimulation of one pathway usually inhibits the other.
• Key Regulatory Enzymes:
  • Glycogen Synthase: Exists in active dephosphorylated (a) and inactive phosphorylated (b) forms.
  • Phosphorylase: Exists in active phosphorylated (a) and inactive dephosphorylated (b) forms.

Regulation During Fasting

• Blood glucose decreases, causing secretion of epinephrine and glucagon.
• Hormones bind to cell membrane receptors activating adenylate cyclase.
• Adenylate cyclase produces cAMP from ATP.
• cAMP activates cAMP-dependent protein kinase.
• Protein kinases phosphorylate glycogen synthase, inhibiting glycogen synthesis, and phosphorylating phosphorylase kinase, activating glycogen degradation (glycogenolysis).

Regulation After Meals

• Blood glucose levels increase, stimulating insulin release.
• Insulin promotes glycogen synthesis and inhibits glycogenolysis.
• Phosphodiesterase breaks down cAMP into 5' AMP, reducing protein kinase activation.
• Phosphatases remove phosphate groups from glycogen synthase, activating it, and from phosphorylase, inhibiting glycogenolysis.