CTPsynthase

CTP synthase (CTPS) is an enzyme that catalyzes the ATP- and ammonia-dependent amination of uridine triphosphate (UTP) to form cytidine triphosphate (CTP). It plays a central role in de novo pyrimidine nucleotide biosynthesis, providing CTP required for RNA and DNA synthesis and for phospholipid production.

Biochemical mechanism and structure: CTPS contains two functional domains: an N-terminal glutaminase domain that hydrolyzes glutamine to produce ammonia, and a C-terminal synthetase domain that uses the ammonia to convert UTP into CTP. The two domains are connected by an intramolecular ammonia tunnel that channels the NH3 from glutamine hydrolysis to the synthetase site. ATP is used to activate UTP in the course of the reaction, driving the formation of CTP.

Genetics and distribution: In bacteria, the enzyme is typically encoded by the pyrG gene. In eukaryotes, multiple CTPS genes are common, such as CTPS1 and CTPS2 in mammals, and URA7/URA8 in yeast. CTPS is essential for the maintenance of cellular nucleotide pools in many organisms.

Regulation and cellular organization: CTPS activity is regulated by cellular nucleotide levels, notably through feedback inhibition by CTP. The enzyme can also assemble into filamentous structures called cytoophidia in a variety of organisms; polymerization into these filaments is influenced by metabolic state and environmental conditions and is thought to modulate enzymatic activity.

Clinical and research relevance: CTPS is of interest as a potential target in antimicrobial and anticancer strategies, with research exploring inhibitors that target either the glutaminase or synthetase activities. The dynamic organization of CTPS into cytoophidia also provides a model for understanding metabolic regulation and enzyme compartmentalization in cells.

---