Overview
Lecture explains amino acid metabolism focusing on transamination in muscle, oxidative deamination in liver, energy and glucose production, and clinical relevance of ALT/AST.
Transamination: Concept and Mechanism
- Definition: Transfer of an amine group from an amino acid to a keto acid.
- Cofactor: Pyridoxal phosphate (PLP), derived from vitamin B6; forms a Schiff base (imine) with enzyme.
- Enzyme class: Aminotransferases (transaminases); reactions are reversible.
Alanine + α-Ketoglutarate
- Alanine donates its amine to α-ketoglutarate; oxygen swaps to alanine.
- Products: Pyruvate (from alanine) and glutamate (from α-ketoglutarate).
- Enzyme: Alanine aminotransferase (ALT; also called alanine aminotransferase/transaminase).
Aspartate + α-Ketoglutarate
- Aspartate donates its amine to α-ketoglutarate; oxygen swaps to aspartate.
- Products: Oxaloacetate (from aspartate) and glutamate (from α-ketoglutarate).
- Enzyme: Aspartate aminotransferase (AST; aspartate aminotransferase/transaminase).
Transamination: Key Structural Notes
- PLP mediates amine transfer via Schiff base linkage to enzyme active-site lysine.
- Swapped groups: Amine (from amino acid) and carbonyl oxygen (from keto acid).
Fate of Pyruvate in Muscle
- Converts to lactate under anaerobic conditions via lactate dehydrogenase; generates NAD+ from NADH.
- Converts to acetyl-CoA to enter TCA cycle; proceeds to electron transport chain for ATP production.
Cori Cycle and Gluconeogenesis
- Lactate released to blood, taken by liver, converted to pyruvate (lactate dehydrogenase; NAD+ to NADH).
- Pyruvate converted to glucose-6-phosphate, then to free glucose (glucose-6-phosphatase in liver).
- Purpose: Supports gluconeogenesis and returns glucose to muscle.
Oxidative Deamination in Liver
- Substrate: Glutamate transported from muscle/other tissues to liver.
- Enzyme: Glutamate dehydrogenase.
- Cofactors: Uses NADP+ to form NADPH; adds water in a two-step mechanism (presented as net step).
- Products: α-Ketoglutarate regenerated and free ammonia (NH3), which is toxic.
- Ammonia handling: NH3 + H+ â NH4+; enters mitochondria for urea cycle (detailed elsewhere).
- Location: Mainly liver; can occur in other tissues less significantly.
Integration with TCA Cycle and Energy/Glucose Production
- Transamination generates TCA intermediates: pyruvate, oxaloacetate, α-ketoglutarate.
- Amino acids can feed at multiple TCA/transition points:
- Tyrosine â fumarate.
- Valine â succinyl-CoA.
- Leucine â acetoacetate/acetyl-CoA (acetoacetyl-CoA/acetyl-CoA equivalent).
- Significance:
- ATP production through TCA cycle and oxidative phosphorylation.
- Gluconeogenesis: OAA â malate (shuttle) â OAA â PEP (PEPCK) â glucose.
Reversibility and Network Flow
- ALT and AST reactions are reversible.
- Glutamate + pyruvate â alanine + α-ketoglutarate.
- Glutamate + oxaloacetate â aspartate + α-ketoglutarate.
- Many amino acids interconvert to TCA intermediates via transamination.
Clinical Relevance of Transaminases
- Tissue distribution: Heart, skeletal muscle, liver.
- Injury marker:
- Elevated AST ± ALT: Suggests liver damage.
- Elevated ALT (and creatine kinase, troponin): Suggests cardiac or skeletal muscle injury; may indicate myocardial infarction.
Structured Summary
| Process/Enzyme | Substrates | Cofactor | Products | Location | Notes/Significance |
|---|
| ALT (alanine aminotransferase) | Alanine + α-ketoglutarate | PLP (vitamin B6) | Pyruvate + Glutamate | Muscle, liver, heart | Reversible; forms pyruvate for ATP or lactate; clinical marker (ALT) |
| AST (aspartate aminotransferase) | Aspartate + α-ketoglutarate | PLP (vitamin B6) | Oxaloacetate + Glutamate | Muscle, liver, heart | Reversible; generates OAA for TCA/gluconeogenesis; clinical marker (AST) |
| Lactate dehydrogenase | Pyruvate + NADH | â | Lactate + NAD+ | Muscle; liver (reverse) | Supports anaerobic glycolysis; Cori cycle in liver converts lactate â pyruvate |
| Glucose-6-phosphatase | Glucose-6-phosphate | â | Glucose + Pi | Liver | Final step of hepatic gluconeogenesis; supplies blood glucose |
| Glutamate dehydrogenase | Glutamate + NADP+ + H2O | â | α-Ketoglutarate + NADPH + NH3 | Mainly liver | Oxidative deamination; generates toxic NH3 for urea cycle; produces NADPH |
| PEPCK | Oxaloacetate + GTP | â | PEP + GDP + CO2 | Cytosol (pathway context) | Key gluconeogenic step from OAA to PEP |
Key Terms & Definitions
- Transamination: Transfer of an amine group from an amino acid to a keto acid.
- Pyridoxal phosphate (PLP): Vitamin B6-derived cofactor; forms Schiff base with enzyme.
- Schiff base (imine): Carbon-nitrogen double bond linking PLP to enzyme active site.
- Oxidative deamination: Removal of an amine from glutamate, producing NH3 and α-ketoglutarate.
- Cori cycle: Muscle-to-liver lactate shuttle for gluconeogenesis.
- Gluconeogenesis: Glucose synthesis from non-carbohydrate sources (e.g., amino acids).
- NADPH: Reducing agent used in fatty acid synthesis and free radical reactions.
- α-Ketoglutarate: TCA intermediate; key keto acid in transamination.
- Oxaloacetate (OAA): TCA intermediate; gluconeogenic precursor via PEPCK.
Action Items / Next Steps
- Understand ALT/AST mechanisms, substrates, and reversibility.
- Trace flows: alanine/aspartate to TCA intermediates and onward to ATP/glucose.
- Review handling of ammonia via urea cycle (covered in subsequent lecture).
- Relate elevated ALT/AST to tissue injury patterns in clinical scenarios.