Amino Acid Degradation/Urea Cycle - 30

Outline of Amino Acid Degradation and the Urea Cycle

• Removal of nitrogen from amino acids

• Processing of ammonium

• Using carbons from amino acids

Proteins and Amino Acids

• The body processes large quantities of amino acids daily due to:

  • Cellular protein turnover: This is significant as proteins are continuously being synthesized and degraded.

  • Sources of Amino Acids:

  • Ingested proteins

  • Recycled proteins

• Metabolic Challenges:

  • Approx. 100 g of ingested protein daily

  • No storage form exists for amino acids, making balance crucial

  • Excess nitrogen is toxic, necessitating removal for safety

  • Diversity in side chains impacts metabolism pathways

Amino Acid Degradation: Removal of Nitrogen

• Site of Degradation:

  • Primarily occurs in the liver (exception: branched-chain amino acids are utilized in muscle tissue).

• Initial Step: Nitrogen removal to create α-keto acids:

  • Enzymes involved:

  • Aminotransferases (Transaminases): Most amino acids lose nitrogen through these enzymes.

    • Transfer NH3 to α-ketoglutarate to form glutamate.

  • Dehydrogenase for glutamate processing

  • Dehydratase for serine and threonine

Amino Acid Degradation: Transaminases

• Functioning of Aminotransferases:

  • Transfers NH3 to α-ketoglutarate → forms glutamate.

  • Examples of Reactions:

  • Alanine aminotransferase:

    • Converts alanine to pyruvate:
      ext{alanine} + ext{α-ketoglutarate}
      ightarrow ext{pyruvate} + ext{glutamate}

  • Aspartate aminotransferase:

    • Converts aspartate to oxaloacetate:
      ext{aspartate} + ext{α-ketoglutarate}
      ightarrow ext{oxaloacetate} + ext{glutamate}

Amino Acid Degradation: Production of Ammonium

• Conversion of excess nitrogen to ammonium (NH4+) occurs in mitochondria.

• Contribution from deamination of amino acids results in glutamate production.

  • Release of nitrogen as ammonium mediated by glutamate dehydrogenase:
    ext{glutamate} + ext{NAD+}
    ightarrow ext{α-ketoglutarate} + ext{NH4+} + ext{NADH}

  • Notes on clinical relevance: High blood transaminases signal liver damage.

The Urea Cycle: Overview

• Ureotelic organisms (e.g., most terrestrial vertebrates) excrete excess NH4+ as urea.

• Urea is synthesized from:

  • Ammonium (NH4+)

  • Bicarbonate (HCO3-)

  • Aspartate (source of NH3)

• Starting Point: Initiates in mitochondria, catalyzed by carbamoyl phosphate synthetase (CPS I) which combines NH4+ and bicarbonate.

Urea Cycle: Mitochondrial Reactions

• CPS I** activity requires hydrolysis of two ATP (irreversible).

• Activation occurs in mammals through N-acetylglutamate, indicating free amino acids:
  ext{NH4+} + ext{HCO3-} + 2 ext{ATP}
  ightarrow ext{carbamoyl phosphate} + 2 ext{ADP} + ext{Pi}

• Carbamoyl phosphate converts to citrulline via a transfer to ornithine.

Urea Cycle: Cytoplasmic Reactions

• Citrulline moves to cytoplasm where combined with aspartate by arginosuccinate synthetase:

  • ATP is cleaved driving the reaction:

  • Argininosuccinate is split into arginine and fumarate:
    ext{citrulline} + ext{aspartate} + ext{ATP}
    ightarrow ext{argininosuccinate}
    ightarrow ext{arginine} + ext{fumarate}

• Arginine is cleaved to produce urea and ornithine.

Energetics of Nitrogen Removal

• The incorporation of two NH4+ in urea costs four phosphate bonds:

  • Converting three ATP to two ADP and one AMP shows high energetic cost.

• Fumarate entering the citric cycle has implications for gluconeogenesis and aspartate production:

  • Oxaloacetate can convert to glucose or transaminated to aspartate.

Clinical Insights

• Urea Cycle Defects:

  • Any defect leads to hyperammonemia, often lethal, as no alternate urea formation pathway exists.

  • Occurrence rate: 1 in 15,000 births.

• Excessive alcohol intake can also cause hyperammonemia due to increased NADH production leading to tissue damage.

Alternative Strategies for Nitrogen Disposal

• Most terrestrial vertebrates excrete nitrogen as urea (ureotelic).

• Aquatic animals are generally ammoniotelic, excreting nitrogen as ammonium due to rapid dilution.

• Birds excrete nitrogen as uric acid (uricotelic), which is more energy-intensive but conserves water.

• Example: Bears recycle urea during hibernation for amino acid production.

Processing of Amino Acid Carbon Skeletons

• Carbon skeletons convert into metabolic intermediates:

  • Options include pyruvate, acetyl CoA, α-ketoglutarate, and more.

• Pathways exhibit complexity due to structural diversity of amino acids and different degradation routes.

Specific Examples: Amino Acid Conversions

• Amino Acids to Pyruvate:

  • Direction conversion through aminotransferases results in urgent metabolites.

• Glutamate Conversion: Converted to α-ketoglutarate for citric acid cycle entry.

• Branched-chain Amino Acids:

  • Degraded to acetyl CoA, acetoacetate, and succinyl CoA.

  • Leucine involves a series of transaminations and decarboxylations to achieve this shift.

Clinical Insight: Diseases from Amino Acid Degradation

• Phenylketonuria: Caused by a defect in phenylalanine hydroxylase critical for tyrosine conversion, leading to cognitive disabilities without dietary management.

Key Points for Review

• Understand role of enzymes like transaminases, dehydratases, and dehydrogenases in amino acid degradation.

• Know pathways related to urea cycle and metabolic interconnections with gluconeogenesis.

• Familiarize with the distinction between glucogenic and ketogenic amino acids and related pathways.

• Be aware of clinical conditions like phenylketonuria and implications on diet and health.