Urea Cycle

Urea Cycle

• Metabolic pathway that converts toxic ammonia (NH₃) into urea.

• Prevents ammonia accumulation in the body

• Produces Urea

Liver

Organ where the urea cycle occurs primarily.

Ornithine Cycle and Krebs-Henseleit Cycle

Synonyms for Urea Cycle

Kidney

Organ that excretes Urea

Primary Function of the Urea Cycle

• Detoxifies ammonia produced during amino acid metabolism

• Converts nitrogen waste into a less toxic form (urea)

• Maintains nitrogen balance in the body

Ammonia

• NH₃

• Toxic nitrogen-containing waste product

• Generated during amino acid breakdown

• Highly toxic to the nervous system

• Converted into urea by the urea cycle

Urea

• CO(NH₂)₂

• Water-soluble molecule

• Main nitrogenous waste product in humans

Liver cells (Hepatocytes)

Cells where the UREA Cycle takes place.

Mitochondria

Where do the first two reactions of the Urea Cycle occur?

Cytosol

Where do the remaining reactions after the first two reactions of the Urea Cycle occur?

Mitochondrial Reactions of the Urea Cycle

• Formation of carbamoyl phosphate

• Formation of citrulline

• Occur inside the mitochondrial matrix

Cytosolic Reactions of the Urea Cycle

• Formation of argininosuccinate

• Formation of arginine

• Formation of urea and regeneration of ornithine

Carbamoyl phosphate

• CH₂NO₅P²⁻

• First intermediate of the urea cycle

• Formed from ammonia and bicarbonate

• Requires ATP

• Produced by carbamoyl phosphate synthetase I (CPS I)

Carbamoyl Phosphate Synthetase I (CPS I)

• Catalyzes the first committed step of the urea cycle

• Located in mitochondria

• Combines NH₃, HCO₃⁻, and ATP

• Activated by N-acetylglutamate

N-Acetylglutamate (NAG)

• Essential activator of CPS I

• Increases urea cycle activity

• Synthesized from glutamate and acetyl-CoA

• Signals high amino acid metabolism

Ornithine

• C₅H₁₂N₂O₂

• Amino acid-like molecule

• Accepts carbamoyl phosphate to form citrulline

• Regenerated at the end of the cycle

• Functions as a carrier molecule

Ornithine Transcarbamylase (OTC)

• Enzyme that combines ornithine and carbamoyl phosphate

• Produces citrulline

• Located in mitochondria

• Deficiency causes hyperammonemia

Citrulline

• C₆H₁₃N₃O₃

• Intermediate of the urea cycle

• Formed from ornithine and carbamoyl phosphate

• Transported from mitochondria to cytosol

• Combines with aspartate in the next step

Aspartate

• C₄H₇NO₄

• Provides the second nitrogen atom of urea.

• Combines with citrulline

• Derived from amino acid metabolism

Argininosuccinate

• C₁₀H₁₈N₄O₆

• Intermediate formed from citrulline and aspartate

• Produced using ATP

• Precursor of arginine

Argininosuccinate Synthetase

• Catalyzes formation of argininosuccinate

• Uses citrulline, aspartate, and ATP

• Located in the cytosol

Argininosuccinate Lyase

• Splits argininosuccinate

• Produces arginine and fumarate

• Connects the urea cycle with the citric acid cycle

Fumarate

• C₄H₄O₄

• Byproduct of argininosuccinate breakdown

• Intermediate of the citric acid cycle

• Can be converted to malate and oxaloacetate

Aspartate-Argininosuccinate Shunt

• Metabolic link between the urea cycle and citric acid cycle.

• Transfers carbon skeletons and nitrogen

• Involves fumarate, malate, oxaloacetate, and aspartate

Arginine

• C₆H₁₄N₄O₂

• Intermediate of the urea cycle

• Hydrolyzed to produce urea

• Regenerates ornithine

• Semi-essential amino acid

Arginase

• C₃₃₄H₅₅₄N₉₆O₁₃₄S₄Mn₂

• Final enzyme of the urea cycle

• Converts arginine into urea and ornithine

• Located in the cytosol

• Highly expressed in the liver

Final Reaction of the Urea Cycle

• Arginine + H₂O → Urea + Ornithine

• Catalyzed by arginase

• Releases urea for excretion

Overall Urea Cycle Equation

• NH₃ + CO₂ + Aspartate + 3 ATP + H₂O

• → Urea + Fumarate + 2 ADP + AMP + 2 Pi + PPi

• Net result is removal of two nitrogen atoms

Nitrogen Sources of Urea

• One nitrogen comes from free ammonia (NH₃)

• One nitrogen comes from aspartate

• Carbon comes from bicarbonate (HCO₃⁻)

Carbon Source of Urea

• Carbon atom originates from bicarbonate (HCO₃⁻).

• Incorporated during carbamoyl phosphate synthesis

ATP Requirement of the Urea Cycle

• Consumes 3 ATP molecules

• Equivalent to 4 high-energy phosphate bonds.

• Makes the pathway energetically expensive

Hyperammonemia

• Elevated ammonia levels in blood.

• Can result from urea cycle defects

• Causes neurological dysfunction

• Medical emergency in severe cases

Urea Cycle Disorder (UCD)

• Genetic defect in a urea cycle enzyme

• Causes impaired ammonia detoxification

• Leads to hyperammonemia

• Often presents in infancy or childhood

Ornithine Transcarbamylase Deficiency

• Most common urea cycle disorder

• X-linked inheritance

• Causes ammonia accumulation

• Leads to increased orotic acid production

Hyperammonemia Symptoms

• Vomiting

• Lethargy

• Confusion

• Seizures

• Coma in severe cases

Rate-Limiting Step of the Urea Cycle

• Formation of carbamoyl phosphate

• Catalyzed by CPS I

• Regulated by N-acetylglutamate

Carbamoyl Phosphate Synthetase I (CPS I), Ornithine Transcarbamylase (OTC), Argininosuccinate Synthetase, Argininosuccinate Lyase, and Arginase

Order of Enzymes in the Urea Cycle

Ammonia + carbon dioxide, carbamoyl phosphate, ornithine, citrulline, argininosuccinate, arginine, urea + ornithine

Order of Intermediates in the Urea Cycle

Carbamoyl phosphate, Ornithine, Citrulline, Argininosuccinate, Arginine, Urea

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Orotic acid

• C₅H₄N₂O₄

• A molecule used by the body to make DNA and RNA building blocks (pyrimidines)