Lecture 2.1 - Energy production (carbohydrate 1-2)

Carbohydrate Metabolism

• Hyperlactatemia: 2-5mM lactate, below renal threshold, no change in pH, kidneys can dispose of lactate
• Lactic acidosis: >5mM lactate, above renal threshold, blood pH lowered

Pentose Phosphate Pathway (Hexose Monophosphate Shunt)

• Not all glucose 6-phosphate enters glycolysis, some is metabolized via the pentose phosphate pathway (oxidative, no ATP produced)
• Important pathway for liver, red blood cells, and adipose tissue
• Functions:
  • Produce NADPH (reducing power for anabolic processes such as lipid synthesis)
  • Maintain free -SH (thiol) groups on cysteine residues in certain proteins (important in G6PDH deficiency)
  • Produce C5-sugar ribose for nucleotide synthesis (DNA and RNA)

Galactose Metabolism

• Galactose is required for the synthesis of glycolipids and glycoproteins (e.g., blood group antigens A, B, and O)
• Dietary lactose is hydrolysed by lactase to release glucose and galactose, which are absorbed into the bloodstream
• Galactose is metabolized largely in the liver (some in the kidney and GI tract)
• Lactose = galactose + glucose

Galactosemia

• Genetic condition with 2 variants: classical galactosemia (deficiency of galactose 1-P uridyltransferase) and non-classical galactosemia (deficiency of galactokinase)
• Accumulation of galactose leads to accumulation of galactitol, which utilizes NADPH, depleting NADPH from tissues
• Patient safety: galactosemia should be detected in early life for effective management

Catabolism of Carbohydrates - Stage 2

• Intracellular (cytosol): glycolysis/pentose phosphate pathway
• Intracellular (mitochondria): connecting stage 2-3
• Phase 1 (reactions 1-3): energy investment (2 moles ATP per 1 mol glucose)
• Phase 2 (reactions 4-10): energy production (4 moles ATP per 1 mol glucose)
• Functions:
  • Yields NADH (reducing power)
  • ATP produced from ADP (net: 2 moles ATP per mol glucose)
  • Produces C6 and C3 intermediates (links to other metabolic pathways)
• Features:
  • Exergonic (reactions 7 and 10 generate ATP)
  • C6 (glucose) generates 2 C3 (pyruvate)
  • Lactate from pyruvate can be generated in the absence of oxygen

Lactate Dehydrogenase Reaction

• Occurs in cells with limiting oxygen availability (RBC, skeletal muscle, brain, skin, and GI)
• Lactate released into blood and metabolized in the liver and heart, and is disposed of by the kidneys
• Regenerates NAD+ needed for glycolysis when NADH is being used up
• Blood levels < 1mM

Clinical Relevance - Stage 2

• Glycolysis needs NAD+ to oxidize glucose
• As total NAD+ and NADH is constant, when all NAD+ is converted to NADH, glycolysis stops
• NAD+ needs to be regenerated by another route
• Glycolysis intermediates are important for other metabolic routes:
  • Triglyceride and phospholipid synthesis
  • Regulator of oxygen affinity to hemoglobin

Catabolism of Carbohydrates - Stage 1

• GI tract (extracellular): breakdown and absorption
• Breakdown: hydrolysis of glycosidic bonds to glucose, galactose, and fructose
• GI tract enzymes: glycosidases (amylases)
• Saliva: amylase (starch, glycogen -> dextrins)
• Pancreas: amylase (major enzyme)
• Small intestine: disaccharides attached to brush border membrane of epithelial cells
• No significant hydrolysis of cellulose, no enzymes to attack the beta 1-4 linkages

Clinical Relevance - Stage 1

• Glucose requirements of tissues:
  • Major sugar in blood
  • All tissues can metabolize glucose
  • Blood glucose regulated (~5 mM) by hormonal regulation (insulin, glucagon)
  • Some tissues (RBC, lens of eye) have an absolute requirement on glucose
  • Uptake by these tissues depends on blood glucose
  • CNS (brain) prefers glucose and cannot metabolize fatty acids
  • Some tissues need it for specialized functions (liver, adipose)