Amino Acid Metabolism and Urea Cycle

Posted on Feb 9, 2025 in Human Nutrition and Dietetics

Essential and Non-Essential Amino Acids

Essential Amino Acids: Isoleucine (Ile), Leucine (Leu), Valine (Val), Threonine (Thr), Methionine (Met), Cysteine (Cys), Tryptophan (Trp), Phenylalanine (Phe), Tyrosine (Tyr), Lysine (Lys), Arginine (Arg), Histidine (His).
Non-essential Amino Acids: Alanine (Ala), Asparagine (Asn), Aspartate (Asp), Glutamate (Glu), Glycine (Gly), Proline (Pro), Serine (Ser).

Ammonia Elimination

Organisms eliminate ammonia through different mechanisms:

  • Ammonotelic: Excretion of ammonia (aquatic organisms).
  • Ureotelic: Excretion of urea (terrestrial animals like snakes, amphibians, and mammals).
  • Purinotelic: Excretion of purines (reptiles and birds).

Amino Acid Metabolism: Sources and Uses

Intracellular Amino Acid Pool

The intracellular amino acid pool has multiple sources and uses:

Sources of the Pool

  • Exogenous Proteins:
    • [Stomach] (Pepsin, HCl) -> Major polypeptides.
    • [Lumen] (Endo/exopeptidases) -> Small peptides + amino acids.
    • [Intestinal absorption] (Di/aminopeptidases) -> Amino acids in intestinal cells, then blood.
  • Metabolic Precursors: From various metabolic pathways.
  • Endogenous Proteins: From lysosomal/cytoplasmic proteolysis (protein turnover).

Uses of the Pool

  • Endogenous Protein Synthesis: Ribosomal biosynthesis.
  • Non-protein Peptides with Specific Actions: Glutathione, oxytocin, vasopressin, etc.
  • Purine and Pyrimidine Bases: Nucleosides (nucleic acids, NTPs, coenzymes, etc.).
  • Porphyrin Ring: Cytochromes, hemoglobin (leading to bile pigments).
  • Membrane Lipids: Phosphoglycerides, sphingosine.
  • Neurotransmitters: GABA, serotonin, acetylcholine.
  • Hormones: Thyroxine, epinephrine, other catecholamines.
  • Other Biological Amines: Histamine, melanin, spermine, dopamine.

Surplus Amino Acids

Excess amino acids are processed:

  • NH4+: Goes to the liver to form urea, which is excreted in urine.
  • Carbon Skeleton: Used for energy, becoming pyruvate or entering the citric acid cycle via acetyl-CoA.

Protein Turnover

Protein turnover is crucial for storing nutrients, removing abnormal proteins, and regulating cellular metabolism.

Lysosomal Degradation

Involves around 50 hydrolytic enzymes, including Cathepsins (active at acidic pH).

Cytosolic Degradation

Involves proteases activated by Ca2+:

  • Calpain.
  • Large neutral proteases.
  • Proteasome (ATP-dependent) with ubiquitination (E1 -> E2 via thiol group, Lys) x3/4.

Reasons for degradation: Oxidized residues, N-terminal peptides, PEST sequences.

Amino Acid Metabolism Reactions

Occurs mainly in the liver (70-80%), skeletal muscle, and adipose tissue.

Common Reactions

Separation of the amino group from the carbon skeleton.

Specific Reactions

Biosynthesis and degradation of carbon skeletons, synthesis of nitrogen compounds.

1. Deamination

Transamination

[Amino acid 1 + Keto acid 2 <–> (Transaminase) <–> Keto acid 1 + Amino acid 2]

  • (Keto acid 2: Ketoglutarate; Amino acid 2: Glutamate).
  • (Keto acid 2: Oxaloacetate; Amino acid 2: Aspartate).
  • (Keto acid 2: Pyruvate; Amino acid 2: Alanine [Alanine goes from muscle to liver/ Pyruvate -> Glucose goes from liver to muscle]).

Oxidative Deamination

[Glutamate – [(Glutamate dehydrogenase) + H2O + NAD(P)+ -> NAD(P)H + H+ + NH4+ – GTP + ADP] -> α-Ketoglutarate]

Minor pathway: Amino acid – [(L-amino acid oxidase) + FAD -> FADH2] -> Keto acid + NH4+

Ammonium Transport

A) Conversion of Glutamate to Glutamine

Glutamate – [(Glutamine synthetase) + NH4+ + ATP -> ADP + Pi] -> Glutamine – [Liver (Glutaminase) + H2O -> NH4+] -> Glutamate.

B) Alanine-Glutamate Cycle

C) γ-Glutamyl Cycle

Glutathione – [External side of membrane + Amino acid -> Cys-Gly] -> γ-Glutamyl-amino acid – [Inner membrane – Amino acid in cell] -> Pyroglutamate – [(Pyroglutaminase) + ATP -> ADP + Pi] -> Glutamate – [+ Cys + ATP -> ADP + Pi] -> γ-Glu-Cys – [+ Gly + ATP -> ADP + Pi] -> Glutathione.

Urea Cycle

1. Acquisition of the First Nitrogen Atom

CO2 (from the citric acid cycle) + NH4+ – [(Carbamoyl phosphate synthetase I) + 2 ATP -> 2ADP + Pi] -> Carbamoyl phosphate.

2. Start of the Cycle: Production of Citrulline

Carbamoyl phosphate + Ornithine – [(Ornithine transcarbamoylase) -> Pi] -> Citrulline (leaves mitochondria).

3. Incorporation of the Second Nitrogen Atom

Citrulline – [(Argininosuccinate synthase) + Aspartate + ATP -> PPi (consuming 2 ATP)] -> Argininosuccinate.

4. Cleavage of Argininosuccinate

Argininosuccinate – [(Argininosuccinate lyase) – Fumarate – (Fumarase + H2O) -> L-Malate – (Malate dehydrogenase + NAD+ -> NADH + H+) -> Oxaloacetate – (+ Amino acid -> Keto acid) -> Aspartate (goes to step 3)] -> Arginine.

5. Release of Urea

Arginine + H2O -> Urea + Ornithine (enters mitochondria for step 2).