18.1 Amino Acid Degradation and Urea Cycle

Amino acid breakdown and the urea cycle are crucial for managing nitrogen in our bodies. These processes convert excess amino acids into harmless urea, preventing toxic ammonia buildup. Without them, we'd be in serious trouble.

Enzymes play key roles in these pathways, moving amino groups around and creating urea. When things go wrong, like in urea cycle disorders, it can lead to dangerous ammonia levels and serious health issues.

Amino Acid Degradation

Transamination and Oxidative Deamination Processes

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• Transamination transfers amino groups between amino acids and α-keto acids
• Aminotransferases (transaminases) catalyze transamination reactions
• Pyridoxal phosphate serves as a coenzyme in transamination reactions
• Oxidative deamination removes amino groups from amino acids, forming ammonia
• Glutamate dehydrogenase catalyzes oxidative deamination of glutamate
• NAD+ or NADP+ act as electron acceptors in oxidative deamination

Ammonia Production and Toxicity

• Ammonia produced from amino acid degradation requires rapid removal
• Glutamate dehydrogenase plays a central role in ammonia production
• Ammonia toxicity affects the central nervous system
• High ammonia levels can lead to confusion, lethargy, and coma
• The brain is particularly sensitive to ammonia accumulation
• Ammonia interferes with neurotransmitter function and energy metabolism

Urea Cycle Overview

Urea Cycle Enzymes and Reactions

• Urea cycle converts toxic ammonia into urea for excretion
• Carbamoyl phosphate synthetase I initiates the urea cycle in mitochondria
• Ornithine transcarbamoylase catalyzes the formation of citrulline from ornithine and carbamoyl phosphate
• Argininosuccinate synthetase combines citrulline with aspartate to form argininosuccinate
• Argininosuccinate lyase cleaves argininosuccinate into arginine and fumarate
• Arginase hydrolyzes arginine to produce urea and regenerate ornithine

Urea Cycle Regulation and Energy Requirements

• N-acetylglutamate acts as an allosteric activator of carbamoyl phosphate synthetase I
• The urea cycle consumes 4 ATP molecules per urea molecule produced
• Aspartate provides one of the nitrogen atoms for urea formation
• The urea cycle occurs partially in mitochondria and partially in the cytosol
• Ornithine and citrulline transporters facilitate movement between mitochondria and cytosol
• The urea cycle is tightly regulated to maintain nitrogen balance

Urea Cycle Disorders

Hyperammonemia and Its Consequences

• Hyperammonemia results from defects in urea cycle enzymes or transporters
• Elevated blood ammonia levels characterize hyperammonemia
• Symptoms include vomiting, lethargy, seizures, and developmental delays
• Severe hyperammonemia can lead to brain damage or death
• Diagnosis involves measuring blood ammonia levels and genetic testing
• Treatment aims to reduce ammonia production and enhance its removal

Inborn Errors of the Urea Cycle

• Inborn errors of the urea cycle result from genetic mutations
• Carbamoyl phosphate synthetase I deficiency causes severe hyperammonemia
• Ornithine transcarbamoylase deficiency presents as an X-linked disorder
• Citrullinemia results from argininosuccinate synthetase deficiency
• Argininosuccinic aciduria occurs due to argininosuccinate lyase deficiency
• Arginase deficiency leads to hyperargininemia and neurological symptoms
• Management includes dietary protein restriction and alternative pathway medications