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Overview of the Urea Cycle

Apr 28, 2025

Urea Cycle (Ornithine Cycle)

Introduction

  • Urea Cycle: Also known as the Ornithine Cycle or Krebs-Hensleit Cycle.
    • Discovered by Hans Krebs and Kurt Henslitt.
  • Location: Occurs in the liver due to the presence of the enzyme arginase.
  • Pathway: Partly mitochondrial (first two reactions) and partly cytosolic (next three reactions).

Enzymes and Activation

  • Key Enzymes: Five important enzymes are involved.
    • Carbamoyl phosphate synthase 1 (CPS1)
    • Ornithine transcarbamylase
    • Argininosuccinate synthase
    • Argininosuccinate lyase
    • Arginase
  • Activator: N-acetylglutamate is an allosteric activator for CPS1, referred to as the sixth enzyme in regulation.

Steps in the Urea Cycle

  1. Formation of Carbamoyl Phosphate:
    • Carbon dioxide and ammonia condense in presence of CPS1.
    • Requires 2 ATP molecules; N-acetylglutamate is required as an allosteric activator.
  2. Formation of Citrulline:
    • Carbamoyl phosphate condenses with ornithine to form citrulline via ornithine transcarbamylase.
  3. Formation of Argininosuccinate:
    • Citrulline condenses with aspartate to form argininosuccinate, requiring 2 ATP equivalents (AMP and pyrophosphate).
  4. Formation of Arginine and Fumarate:
    • Argininosuccinate converts to arginine and fumarate through argininosuccinate lyase.
  5. Formation of Urea:
    • Arginine converts to ornithine, releasing urea via arginase.

Disorders of the Urea Cycle

  1. Hyperammonemia Type 1:
    • Due to deficiency of CPS1.
  2. Hyperammonemia Type 2:
    • Due to deficiency of Ornithine transcarbamylase.
  3. Citrullinemia:
    • Due to deficiency of Argininosuccinate synthase.
  4. Argininosuccinate Aciduria:
    • Due to deficiency of Argininosuccinate lyase.
  5. Hyperargininemia:
    • Due to deficiency of Arginase.
  6. HHH Syndrome:
    • Hyperammonemia, hyperornithinemia, and homocitrullinuria due to defect in ornithine transporter (ORNT1 gene).

Energetics

  • ATP Consumption:
    • 4 ATP equivalents consumed in total.
    • Net ATP consumption: 1.5 ATP after the generation of 2.5 ATP by NADH from fumarate conversion in TCA cycle.

Regulation

  • Allosteric Regulation:
    • N-acetylglutamate activates CPS1.
  • Compartmentalization:
    • Mitochondrial and cytosolic steps provide minor regulatory effects.

Clinical Importance

  • Neurological Manifestations:
    • Due to increased NH3 concentration affecting the brain by reducing alpha-ketoglutarate and GABA production, while increasing serotonin production.

Key Exam Topics

  • Frequently asked in university biochemistry exams.
  • Important along with the regulation of blood glucose levels.

This summary highlights key points and details about the urea cycle, its regulation, disorders, and its importance in metabolic pathways and clinical implications.

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