Urea Cycle and Defects with Mnemonics

Mnemonic for Urea Cycle Intermediates

Orange Cola, Coffee, Alcohol of Argentina For Aggressive Urine

urea cycle mnemonic

  1. Orange: Ornithine
  2. Cola: Carbamoyl Phosphate
  3. Coffee: Citrulline
  4. Alcohol: Aspartate (enters cycle)
  5. Argentina: Arginosuccinate
  6. For: Fumarate (leaves cycle)
  7. Aggressive: Arginine
  8. Urine: Urea (leaves cycle)

Structure of Urea


Amide group doesn’t raise the pH of blood, unlike ammonia

Understanding the Urea Cycle

Location of cycle

Hepatocyte (Partially in mitochondria and partially in cytoplasm)

ATPs hydrolyzed


  • 2 by Carbamoyl Phsophate Synthetase
  • 1 by Arginosuccinate Synthetase


urea cycle

1st reaction (Mitochondrial matrix):

1. NH4 (from glutamine) + CO2 = Carbamoyl Phosphate

  • Mediated by Carbamoyl Phosphate Synthetase (requires N-Acetyl Glutamate or NAG as obligate activator)
  • NAG is activated by high protein meal
  • Uses 2 molecules of ATP

2. Carbamoyl group (from Carbamoyl Phosphate) + Ornithine (NAG as precursor) = Citrulline

  • Catalyzed by Ornithine transcarbamylase or OTC

3. Citrulline transporter transports citrulline from mitochondrial matrix to cell cytoplasm

2nd reaction (Cell cytoplasm):

Citrulline + Aspartate = Arginosuccinate

  • Argininosuccinate synthetase + ATP (from beta-oxidation of fatty acids) + citrulline = citrullyl-AMP
  • Citrullyl-AMP + NH4 (from aspartate) = Argininosuccinate

3rd reaction (Cell cytoplasm):

Aginosuccinate = Fumarate (leaves cycle) + Arginine

  • Catalyzed by argininosuccinate lyase

4th reaction (Cell cytoplasm):

Arginine = Urea (enters blood to be delivered to kidney) + Ornithine (completes cycle)

  • Catalyzed by arginase

Defects of Urea Cycle

urea cycle

Features common to both Carbamoyl Phosphate Synthetase and Ornithine Transcarbamoylase Deficiency

1. Onset: Within 1-3 days of birth

2. Accumulation of precursors:

  • Increased blood glutamine
  • Increased ammonia (hyperammonemia):
    • Cerebral edema, lethargy, vomiting, convulsions, hyperventilation
    • Alpha-ketoglutarate is consumed hindering TCA cycle

3. Decreased end-porduct:

  • Blood Urea Nitrogen (BUN) is decreased

Carbamoyl Phospate Synthetase (CPS) Deficiency vs Ornithine Transcarbamoylase (OTC) Deficiency

CPS deficiency:

  • Autosomal recessive
  • No orotic aciduria (No Carbamoyl Phosphate)

OTC deficiency:

  • X-linked recessive
  • Orotic aciduria present

Mechanism of Orotic aciduria in OTC deficiency:

The sequence of events:

  1. ↓ OTC
  2. ↑ Carbamoyl Phosphate
  3. Carbamoyl Phosphate leaks out of mitochondria into cytoplasm
  4. In cytoplasm, Carbamoyl phosphate together with Aspartate forms Carbamoyl Aspartate
  5. Carbamoyl Aspartate forms Orotate which enters pyrimidine synthesis (UMP synthetic pathway)

Orotic Aciduria is also seen in UMP synthase deficiency:

  • However, in UMP synthase deficiency (Hereditary Orotic Aciduria) – Ammonia, Glutamine and BUN levels are normal
  • Megaloblastic anemia is a feature of UMP synthase deficiency
  • In UMP synthase deficiency, Uracil is decreased but in OTC deficiency, Uracil is increased

MCAD deficiency

MCAD deficiency

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