Glutarate—CoA ligase

Glutarate—CoA ligase (also known as glutaryl-CoA synthetase, GCS, or glutaryl-Coenzyme A synthetase) is an enzyme that plays a crucial role in the metabolism of lysine, tryptophan, and hydroxylysine in mammals, including humans. It catalyzes the ATP-dependent ligation of Coenzyme A (CoA) to glutarate, forming glutaryl-CoA, a key intermediate in the degradation pathway of these amino acids. This reaction is essential for the conversion of certain amino acids into energy during metabolic processes.

Function

Glutarate—CoA ligase is involved in the metabolism of lysine, tryptophan, and hydroxylysine, which are important amino acids used by the body to produce proteins, hormones, and other vital molecules. The enzyme facilitates the fifth step in the degradation pathway of these amino acids, converting glutarate into glutaryl-CoA. This conversion is critical for the proper processing and elimination of these amino acids, preventing the accumulation of potentially harmful substances in the body.

Genetics

The gene responsible for encoding glutaryl-CoA synthetase is located on human chromosome 19. Mutations in this gene can lead to a rare metabolic disorder known as glutaric aciduria type 1 (GA1). GA1 is characterized by an accumulation of glutaric acid and its derivatives in the body, which can lead to neurological damage and other severe complications if not diagnosed and managed promptly.

Clinical Significance

Glutaric aciduria type 1 (GA1) is the most significant clinical condition associated with deficiencies in glutaryl-CoA synthetase activity. Early diagnosis and management of GA1 are crucial to prevent the development of severe neurological symptoms, including dystonia, choreoathetosis, and seizures. Dietary management and carnitine supplementation are among the treatments used to manage GA1, aiming to limit the accumulation of toxic metabolites in the body.

Biochemical Pathway

The biochemical pathway involving glutaryl-CoA synthetase is a part of the broader catabolic pathways of lysine, tryptophan, and hydroxylysine. After the initial steps of amino acid degradation, glutarate is produced as an intermediate. Glutarate—CoA ligase then catalyzes the formation of glutaryl-CoA, which is subsequently processed through several more steps before being fully degraded into acetyl-CoA or other metabolites that can enter the citric acid cycle for energy production.

See Also

• Metabolism
• Amino acid degradation
• Citric acid cycle
• Coenzyme A
• Lysine
• Tryptophan