Aspartattranscarbamylase

Aspartate transcarbamylase (ATCase) is a key enzyme in de novo pyrimidine biosynthesis. It catalyzes the condensation of carbamoyl phosphate with aspartate to form N-carbamoyl-L-aspartate and inorganic phosphate. This reaction represents the first committed step in the production of pyrimidine nucleotides.

In many bacteria and archaea, ATCase is part of a regulated holoenzyme that contains catalytic and regulatory subunits. The catalytic subunits carry the active sites, while the regulatory subunits modulate activity in response to cellular nucleotide levels. ATCase is a classic example of allosteric regulation: ATP acts as an activator and CTP as an inhibitor, enabling coordination between purine and pyrimidine pools. Binding of nucleotides induces conformational changes that shift the enzyme between low- and high-activity states.

In eukaryotes, the ATCase activity is typically encoded as a domain within the multifunctional CAD enzyme complex, which also harbors carbamoyl-phosphate synthetase II and dihydroorotase activities. Regulation in these organisms is integrated with broader cellular signaling and nucleotide balance.

Structure and mechanism: ATCase is typically a multimeric enzyme. The catalytic domain achieves the carbamoylation of aspartate using carbamoyl phosphate as the donor, proceeding through a two-step mechanism characteristic of aspartate transcarbamylases. The allosteric regulatory architecture enables cooperative responses to effector molecules, providing tight control over pyrimidine synthesis.

Development and research: ATCase has served as a foundational model for studying allostery and enzyme kinetics, illustrating how regulatory subunits influence catalytic activity and how metabolic signals coordinate nucleotide biosynthesis.