Protein Metabolism
Comprehensive overview of amino acid anabolism (synthesis) and catabolism (degradation)
Protein Anabolism (Amino Acid Synthesis)
Essential vs Non-Essential Amino Acids
Essential Amino Acids (9 total - must be consumed in diet):
Non-Essential Amino Acids (11 total - synthesized in body):
Carbon Skeleton Sources
Non-essential amino acids are synthesized from intermediates of glycolysis and the TCA cycle:
- 3-Phosphoglycerate: → Serine → Glycine, Cysteine
- Pyruvate: → Alanine
- α-Ketoglutarate: → Glutamate → Glutamine, Proline, Arginine
- Oxaloacetate: → Aspartate → Asparagine
Glutamate: Central Hub of Amino Acid Synthesis
Glutamate Dehydrogenase:
α-Ketoglutarate + NH₄⁺ + NADH → Glutamate + NAD⁺
Glutamine Synthetase:
Glutamate + NH₄⁺ + ATP → Glutamine + ADP + Pi
Glutamate and glutamine serve as nitrogen donors for the synthesis of other amino acids, purines, and pyrimidines.
Transamination
Key Reaction: Transfer of amino group from one amino acid to an α-keto acid
Amino Acid 1 + α-Keto Acid 1 ⇌ α-Keto Acid 2 + Amino Acid 2
Important Transaminases:
- AST (Aspartate Aminotransferase):
Glutamate + Oxaloacetate ⇌ α-KG + Aspartate - ALT (Alanine Aminotransferase):
Glutamate + Pyruvate ⇌ α-KG + Alanine
Note: Elevated AST and ALT in blood are clinical markers for liver damage
Methylation Pathway
Methionine, serine, and cysteine metabolism are interconnected:
- Methionine + ATP → SAM (S-adenosylmethionine)
- SAM → Transmethylation (methyl group transfer to DNA, proteins, lipids)
- SAM → SAH → Homocysteine
- Homocysteine + Serine → Cystathionine → Cysteine
Protein Catabolism (Amino Acid Degradation)
When organismal carbohydrate levels are low or excess amino acids are consumed, amino acids are oxidized for energy.
Removing the Amino Group
Two types of reactions remove nitrogen from amino acids:
1. Transamination (most common):
Amino Acid + α-Keto Acid → α-Keto Acid + Amino Acid
Example: Alanine + α-KG → Pyruvate + Glutamate
2. Deamination (releases free ammonia):
Asparagine + H₂O → Aspartate + NH₄⁺
Via Asparaginase enzyme
Glucogenic vs Ketogenic Amino Acids
Glucogenic (14 AAs)
Can become glucose
Yields: Pyruvate or Oxaloacetate
Both (4 AAs)
Can become glucose or ketones
Yields: Both types of intermediates
Ketogenic (2 AAs)
Cannot become glucose
Yields: Acetyl-CoA or Acetoacetyl-CoA
Why Can't Acetyl-CoA Become Glucose?
Acetyl-CoA requires oxaloacetate to enter the TCA cycle. Two carbons are lost as CO₂ in reactions 3 and 4 of the TCA cycle, so there is no net gain of carbon. A ≥4 carbon intermediate is required to enter the TCA cycle for gluconeogenesis.
Entry Points into Energy Metabolism
- Pyruvate: Alanine, Cysteine, Glycine, Serine, Threonine, Tryptophan
- Acetyl-CoA: Leucine, Lysine, Phenylalanine, Tryptophan, Tyrosine
- Acetoacetyl-CoA: Leucine, Lysine, Phenylalanine, Tryptophan, Tyrosine
- α-Ketoglutarate: Arginine, Glutamate, Glutamine, Histidine, Proline
- Succinyl-CoA: Isoleucine, Methionine, Valine
- Fumarate: Aspartate, Phenylalanine, Tyrosine
- Oxaloacetate: Asparagine, Aspartate
Nitrogen Disposal: The Urea Cycle
Why Remove Nitrogenous Waste?
- Ammonia is toxic: NH₃ is a weak base (pKa = 9.4). At physiological pH (~7.4), it becomes protonated to NH₄⁺, which can cause metabolic alkalosis at high concentrations.
- High [NH₄⁺] disrupts metabolism: Drives excess glutamate and glutamine synthesis, which depletes α-ketoglutarate from the TCA cycle.
- Glutamine as neurotransmitter: Excess glutamine can act as a stimulatory neurotransmitter, leading to neurological problems.
Nitrogen Excretion Strategies
Ammonia (NH₃)
Aquatic animals
Highly soluble, easily diffuses into water
Urea
Mammals
Non-toxic, soluble, excreted in urine
Uric Acid
Birds, reptiles
Low solubility, conserves water
The Urea Cycle
Location: Mitochondria (first 2 steps) and Cytosol (remaining steps)
Function: Converts toxic ammonia into urea for excretion
Two Nitrogen Sources for Urea:
- First Nitrogen (from free ammonia):
NH₄⁺ + CO₂ + 2 ATP → Carbamoyl phosphate (Carbamoyl phosphate synthetase I)
Carbamoyl-P + Ornithine → Citrulline (in mitochondria)
Citrulline exported to cytosol
- Second Nitrogen (from aspartate):
Citrulline + Aspartate + ATP → Arginosuccinate + AMP + PPi (= 2 ATP)
Arginosuccinate → Arginine + Fumarate
Arginine + H₂O → Urea + Ornithine
Energy Cost:
- 2 ATP → Carbamoyl phosphate
- 2 ATP (ATP → AMP + PPi) → Arginosuccinate
- Total: 4 ATP per urea molecule
Linking Urea Cycle and TCA Cycle
The two cycles are energetically linked through fumarate:
- Arginosuccinate → Arginine + Fumarate
- Fumarate enters TCA cycle
- Fumarate → Malate → Oxaloacetate (produces 1 NADH → ~2.5 ATP)
- Oxaloacetate + Glutamate → Aspartate + α-KG (via AST)
- Aspartate provides the second nitrogen back to the urea cycle
The NADH produced (~2.5 ATP) helps offset the energy cost of the urea cycle (~4 ATP per urea).
Protein Metabolism Pathways
| Pathway | Location | Energy | Key Enzyme |
|---|---|---|---|
| Transamination | Cytosol / Mitochondria | No ATP required | AST, ALT |
| Glutamine Synthesis | Cytosol | 1 ATP consumed | Glutamine synthetase |
| Glutamate Synthesis | Mitochondria | 1 NADH consumed | Glutamate dehydrogenase |
| Urea Cycle | Mitochondria + Cytosol | 4 ATP consumed | CPS I, Arginosuccinate synthetase |