1-Pyrroline-5-carboxylate dehydrogenase

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1-Pyrroline-5-carboxylate dehydrogenase (P5CDH) is an enzyme that in humans is encoded by the ALDH4A1 gene. This enzyme plays a crucial role in the metabolism of proline, converting pyrroline-5-carboxylate (P5C) into glutamate, a key amino acid involved in protein synthesis and the regulation of osmotic pressure in cells. The reaction catalyzed by P5CDH is an essential step in the urea cycle and proline degradation pathway, highlighting its importance in amino acid metabolism.

Function[edit | edit source]

P5CDH is involved in the mitochondrial pathway of proline degradation. It catalyzes the irreversible oxidation of pyrroline-5-carboxylate to glutamate, utilizing NAD+ or NADP+ as a cofactor. This reaction not only facilitates the conversion of proline to a more versatile amino acid but also contributes to the cellular redox balance and the production of ATP through the citric acid cycle.

Structure[edit | edit source]

The enzyme is a mitochondrial protein that is widely expressed in human tissues, with higher levels observed in the liver and kidneys, organs pivotal in metabolic regulation. The ALDH4A1 gene encoding P5CDH is located on chromosome 1p36, a region associated with various genetic disorders.

Clinical Significance[edit | edit source]

Mutations in the ALDH4A1 gene can lead to a rare metabolic disorder known as Hyperprolinemia type II or P5CDH deficiency. This condition is characterized by an accumulation of P5C and proline in the body, leading to neurological and developmental issues in affected individuals. Symptoms can include seizures, intellectual disability, and sometimes psychiatric manifestations. Diagnosis is typically based on biochemical analysis of bodily fluids, and treatment focuses on managing symptoms, as there is currently no cure for the underlying enzyme deficiency.

Research[edit | edit source]

Research into P5CDH and its associated pathways has implications for understanding various metabolic disorders and developing potential therapeutic strategies. Studies have explored the enzyme's role in stress responses, as proline metabolism is linked to cellular adaptations to osmotic and oxidative stress. Furthermore, given the enzyme's involvement in glutamate production, there is interest in its potential connection to neurological conditions, such as epilepsy and neurodegenerative diseases, where glutamate signaling is disrupted.

See Also[edit | edit source]

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Contributors: Prab R. Tumpati, MD