Cytidine 5'-triphosphate synthetase 2 (CTPS2)

Cytidine 5'-triphosphate synthetase 2 (CTPS2) is a rate-limiting enzyme in the de novo pyrimidine biosynthetic pathway, responsible for the ATP-dependent conversion of UTP to CTP using glutamine or ammonia as a nitrogen source [2.3.1, 2.3.4]. It plays a fundamental role in cellular metabolism by providing the CTP required for DNA replication, RNA transcription, and the synthesis of phospholipids and sialylated glycoproteins [2.3.3, 2.4.1]. While its paralog CTPS1 is the dominant isoform in activated lymphocytes and many cancers, CTPS2 is ubiquitously expressed and serves as a critical compensatory enzyme when CTPS1 activity is insufficient [2.4.1, 3.2.4]. In chronic lymphocytic leukemia (CLL), CTPS2 is often overexpressed and correlates with poor clinical outcomes, where it also modulates the DNA damage response through interactions with BRCA1 [2.1.1, 2.3.3]. Conversely, the loss of CTPS2 in certain solid tumors, such as ovarian and endometrial cancers, creates a synthetic lethal dependency on CTPS1, making these patients ideal candidates for CTPS1-selective inhibitors like dencatistat [2.1.2, 3.3.1]. Pharmacological inhibition of CTPS2, primarily by analogs such as 3-deazauridine and cyclopentenyl cytosine, aims to deplete intracellular CTP pools to arrest tumor growth and enhance the efficacy of other nucleoside antimetabolites [2.2.2, 3.2.4].

Other names

CTP synthase 2CTP synthase IICTP synthetase type 2UTP-ammonia ligase 2GATD5B

Inhibition of CTP synthesis