Aspartate Transcarbamylase
Overview
Aspartate transcarbamylase (ATCase) is an enzyme that plays a crucial role in the biosynthetic pathway of pyrimidines. It catalyzes the first committed step in this pathway, combining carbamoyl phosphate and L-aspartate to form N-carbamoyl-L-aspartate and inorganic phosphate.
Structure
ATCase is a complex multimeric protein composed of two different types of subunits, catalytic and regulatory. The catalytic subunits are responsible for the enzyme's activity, while the regulatory subunits control this activity. The enzyme exists as a dodecamer with a molecular weight of approximately 300,000 Daltons, arranged in two stacked hexameric rings. Each ring is composed of three catalytic dimers and three regulatory dimers, forming a 6-6-6-6 structure.
Function
The primary function of ATCase is to catalyze the condensation of carbamoyl phosphate and L-aspartate to form N-carbamoyl-L-aspartate and inorganic phosphate. This reaction is the first committed step in the biosynthesis of pyrimidines, which are essential components of nucleic acids. In addition to its role in nucleotide biosynthesis, ATCase also plays a key role in the regulation of pyrimidine biosynthesis through its sensitivity to the end products of the pathway.
Regulation
ATCase is an allosteric enzyme, meaning its activity is regulated by small molecules that bind to sites on the enzyme separate from the active site. The enzyme is inhibited by cytidine triphosphate (CTP), the end product of the pyrimidine biosynthesis pathway. This is an example of feedback inhibition, where the final product of a pathway inhibits an earlier step in the pathway to prevent overproduction. ATCase is also activated by adenosine triphosphate (ATP), a purine nucleotide. This interplay between purine and pyrimidine nucleotides helps to maintain a balance between the two types of nucleotides in the cell.
Clinical Significance
Mutations in the gene encoding ATCase can lead to a variety of disorders, including orotic aciduria, a condition characterized by an excess of orotic acid in the urine. This condition can lead to growth retardation, developmental delay, and other health problems. Understanding the structure and function of ATCase can therefore have important implications for the diagnosis and treatment of these disorders.