Dihydrolipoyl transacetylase

Dihydrolipoyl transacetylase is an essential enzyme involved in the metabolism of carbohydrates and fatty acids. It plays a crucial role in the citric acid cycle, also known as the Krebs cycle, which is a central pathway in cellular respiration. This enzyme is responsible for catalyzing the transfer of an acetyl group from acetyl-CoA to lipoamide, a coenzyme that is bound to the enzyme complex.

Structure and Function

Dihydrolipoyl transacetylase is a large protein composed of multiple subunits. In humans, it is encoded by the DLAT gene located on chromosome 11. The enzyme consists of three functional domains: the lipoyl domain, the peripheral subunit-binding domain, and the catalytic domain.

The lipoyl domain contains a covalently attached lipoamide cofactor, which plays a crucial role in the transfer of acetyl groups. This domain undergoes a series of redox reactions, cycling between the oxidized and reduced forms. The peripheral subunit-binding domain is responsible for binding to other subunits of the enzyme complex, forming a larger multienzyme complex known as the pyruvate dehydrogenase complex or the alpha-ketoglutarate dehydrogenase complex.

The catalytic domain of dihydrolipoyl transacetylase is responsible for the transfer of the acetyl group from acetyl-CoA to the lipoyl cofactor. This transfer reaction is a key step in the citric acid cycle, as it generates acetyl-dihydrolipoamide, which is subsequently oxidized to produce acetyl-CoA and reduced lipoamide. The acetyl-CoA can then enter various metabolic pathways, including the citric acid cycle itself or fatty acid synthesis.

Role in Metabolism

Dihydrolipoyl transacetylase is an essential enzyme in cellular metabolism. It is involved in the breakdown of glucose and fatty acids to produce energy in the form of ATP. In the citric acid cycle, it catalyzes the conversion of acetyl-CoA, derived from glucose or fatty acid metabolism, into carbon dioxide and high-energy electrons.

The enzyme is also involved in the regulation of metabolic pathways. It is subject to regulation by various factors, including phosphorylation and allosteric regulation. Phosphorylation of specific residues on the enzyme can modulate its activity, allowing for fine-tuning of metabolic flux. Allosteric regulation by metabolites such as NADH and ATP helps maintain metabolic homeostasis by ensuring that the citric acid cycle operates at an appropriate rate.

Clinical Significance

Mutations in the DLAT gene encoding dihydrolipoyl transacetylase can lead to metabolic disorders. Deficiencies in the enzyme complex, such as pyruvate dehydrogenase complex deficiency, can result in a range of symptoms, including neurological abnormalities, developmental delays, and lactic acidosis. These disorders are often treated through dietary modifications and supplementation with cofactors that can bypass the defective enzyme complex.

References

1. Citric acid cycle 2. Krebs cycle 3. Pyruvate dehydrogenase complex 4. Acetyl-CoA 5. Lipoamide 6. Metabolism 7. ATP 8. NADH 9. Phosphorylation 10. Allosteric regulation Template:Citric acid cycle Template:Krebs cycle