Dicarboxylate—CoA ligase

Dicarboxylate—CoA ligase (also known as succinate—CoA ligase or succinyl-CoA synthetase (SCS)) is an enzyme that belongs to the family of ligases, specifically those forming carbon-sulfur bonds as in coenzyme A ligases. Dicarboxylate—CoA ligase catalyzes the reversible conversion of succinate and CoA (coenzyme A) into succinyl-CoA and adenosine triphosphate (ATP) or guanosine triphosphate (GTP), depending on the organism, in the presence of magnesium ions. This reaction is a key step in the citric acid cycle (also known as the Krebs cycle or TCA cycle), which is a central pathway in cellular respiration.

Function

The primary function of Dicarboxylate—CoA ligase is to facilitate the conversion of succinate, a four-carbon dicarboxylic acid, to succinyl-CoA, a high-energy thioester compound. This conversion is crucial for the citric acid cycle, where it provides a direct link between the metabolic pathways of carbohydrate, fat, and protein metabolism. The energy released in this reaction is conserved in the form of ATP or GTP, which are essential for various cellular processes.

Mechanism

The enzyme operates through a two-step mechanism. In the first step, the enzyme binds to succinate and ATP (or GTP), leading to the formation of succinyl phosphate and ADP (or GDP). In the second step, CoA displaces the phosphate group to form succinyl-CoA. This reaction requires the presence of Mg2+ as a cofactor to proceed.

Structure

Dicarboxylate—CoA ligase is a multimeric enzyme, typically existing as either a dimer or a tetramer. Its structure includes distinct domains for binding succinate, ATP/GTP, and CoA, facilitating the enzyme's catalytic activity. The precise structure and subunit composition can vary among different organisms, reflecting the enzyme's adaptation to specific cellular environments.

Clinical Significance

Alterations in the activity of Dicarboxylate—CoA ligase have been implicated in various metabolic disorders. Given its pivotal role in the citric acid cycle, any dysfunction in this enzyme can lead to disruptions in energy production, potentially contributing to diseases such as mitochondrial diseases, metabolic syndrome, and certain types of cancer. Research into modulating the activity of Dicarboxylate—CoA ligase offers potential therapeutic avenues for treating these conditions.

See also

• Citric acid cycle
• Coenzyme A
• Metabolic pathway
• Mitochondrial disease
• Metabolic syndrome