GCDH

Glutaryl-CoA Dehydrogenase (GCDH)

Glutaryl-CoA dehydrogenase (GCDH) is an enzyme that plays a crucial role in the catabolism of certain amino acids, specifically lysine, hydroxylysine, and tryptophan. It is a mitochondrial matrix enzyme that catalyzes the oxidative decarboxylation of glutaryl-CoA to crotonyl-CoA, a key step in the metabolic pathway.

Structure

GCDH is a flavoprotein that requires flavin adenine dinucleotide (FAD) as a cofactor. The enzyme is encoded by the GCDH gene located on chromosome 19 in humans. The protein is composed of multiple subunits that form a homotetrameric structure, which is essential for its enzymatic activity.

Function

The primary function of GCDH is to facilitate the breakdown of lysine, hydroxylysine, and tryptophan into energy and other metabolites. This process is part of the lysine degradation pathway, which is vital for maintaining amino acid balance and energy production in the body.

Clinical Significance

Mutations in the GCDH gene can lead to a metabolic disorder known as glutaric aciduria type 1 (GA1). This condition is characterized by the accumulation of glutaric acid and other toxic metabolites in the body, leading to neurological damage and other systemic symptoms. Early diagnosis and management are crucial to prevent severe outcomes.

Symptoms of Glutaric Aciduria Type 1

Individuals with GA1 may present with macrocephaly, dystonia, and other neurological impairments. The onset of symptoms typically occurs in infancy or early childhood, often following an acute illness or metabolic stress.

Diagnosis

Diagnosis of GA1 is typically confirmed through genetic testing for mutations in the GCDH gene, along with biochemical tests that detect elevated levels of glutaric acid in the urine.

Treatment

Management of GA1 involves dietary restrictions to limit the intake of lysine and tryptophan, along with supplementation of carnitine and riboflavin. Early intervention and adherence to treatment protocols can significantly improve outcomes for affected individuals.

Research and Future Directions

Ongoing research is focused on understanding the molecular mechanisms of GCDH function and the development of novel therapeutic approaches for GA1. Gene therapy and enzyme replacement therapy are potential future treatments under investigation.

See Also

• Lysine degradation pathway
• Metabolic disorders
• Flavoproteins

References

• Goodman, S. I., & Frerman, F. E. (2001). Glutaryl-CoA dehydrogenase deficiency. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The Metabolic and Molecular Bases of Inherited Disease. 8th ed. New York, NY: McGraw-Hill.
• Zschocke, J., & Hoffmann, G. F. (1999). Glutaric aciduria type I: from clinical, biochemical and molecular diversity to successful therapy. Journal of Inherited Metabolic Disease, 22(4), 381-391.