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Cytidine triphosphate

Cytidine triphosphate (CTP) is a pyrimidine ribonucleoside triphosphate consisting of the nucleoside cytidine—comprising a cytosine base bound to a ribose sugar—and three phosphate groups attached via high-energy phosphoanhydride bonds, with the molecular formula C₉H₁₆N₃O₁₄P₃.^[1] As one of the four canonical ribonucleotides, CTP serves as an essential substrate for RNA synthesis, where it is polymerized into RNA strands by RNA polymerases to contribute cytidine residues.^[1] It also functions as an activated donor of cytidyl groups and energy in multiple biosynthetic reactions, including the formation of phospholipids and glycoproteins, and is structurally analogous to adenosine triphosphate (ATP) but with cytosine replacing adenine.^[2]^[1] The de novo biosynthesis of CTP occurs primarily through the enzyme cytidine triphosphate synthetase (CTPS), a glutamine amidotransferase that catalyzes the ATP-dependent amination of uridine triphosphate (UTP) by transferring the amide nitrogen from glutamine to the O4 position of UTP's uracil ring, yielding CTP, glutamate, and inorganic phosphate.^[3] This rate-limiting step is tightly regulated by feedback inhibition, where CTP competitively binds to the UTP-binding site of CTPS with a dissociation constant (Kᵢ) of approximately 110 μM, preventing overproduction and maintaining intracellular nucleotide pools.^[3] Alternative salvage pathways primarily recycle exogenous cytidine into CTP via kinases such as uridine-cytidine kinase, providing flexibility in nucleotide homeostasis under varying nutritional conditions.^[4] Beyond nucleic acid production, CTP's biochemical roles extend to lipid metabolism, where it reacts with phosphatidate to form CDP-diacylglycerol, the obligatory precursor for synthesizing major membrane phospholipids such as phosphatidylcholine, phosphatidylethanolamine, and phosphatidylserine.^[1] In protein modification, CTP acts as a coenzyme in glycosylation pathways, facilitating the addition of sugar moieties to nascent polypeptides, and supports sialic acid biosynthesis for cell surface glycoconjugates involved in adhesion and immune recognition.^[1]^[5] The hydrolysis of CTP's high-energy bonds also provides phosphate transfer potential in select enzymatic reactions, though less extensively than ATP.^[2] Imbalances in CTP synthesis, often due to CTPS dysregulation, are associated with enhanced cell proliferation in cancers, underscoring its critical role in coordinating growth and metabolic demands.^[3]

Overview

Definition and nomenclature

Cytidine triphosphate (CTP) is a pyrimidine ribonucleotide consisting of a cytosine nucleobase linked to a ribose sugar through a β-N1-glycosidic bond, with three phosphate groups esterified to the 5' carbon of the ribose via a triphosphate chain characterized by two high-energy phosphoanhydride bonds. This configuration renders CTP a high-energy molecule analogous to other nucleoside triphosphates, capable of driving biosynthetic reactions. The molecular formula of CTP is \ce{C9H16N3O14P3}.^[6]^[7] In biochemical nomenclature, CTP is abbreviated as such and formally named cytidine 5'-(tetrahydrogen triphosphate) according to IUPAC conventions, reflecting the specific positioning of the triphosphate moiety at the 5' hydroxyl group of the ribose. It is distinct from deoxycytidine triphosphate (dCTP), which features a deoxyribose sugar and functions primarily in DNA replication, as well as from uridine triphosphate (UTP), a related pyrimidine nucleotide with uracil replacing cytosine as the base. CTP briefly serves as a key precursor in RNA synthesis, where it provides the cytidine units for polymerization.^[6]^[8]

Discovery and history

The early isolation of nucleotides from RNA hydrolysates laid the groundwork for understanding cytidine derivatives. In 1910, Phoebus A. Levene and Walter A. Jacobs reported the isolation of cytidylic acid (cytidine monophosphate) from yeast ribonucleic acid, identifying it as a key component alongside adenylic, guanylic, and uridylic acids through hydrolysis and fractional precipitation techniques. The triphosphate form of cytidine emerged in mid-20th-century studies on nucleotide phosphorylation, building on prior characterizations of ATP and UTP. By the 1950s, enzymatic assays revealed CTP as a high-energy intermediate in metabolic pathways, notably in Eugene P. Kennedy's 1956 demonstration of its essential role in activating phosphocholine and phosphoethanolamine for phospholipid synthesis in liver extracts.^[9] This work extended phosphorylation research to pyrimidines, confirming CTP's structural analogy to other nucleoside triphosphates. Further biochemical characterization in the 1960s pinpointed the enzyme catalyzing CTP formation. Robert B. Hurlbert and Howard O. Kammen first demonstrated in vitro synthesis of cytidine nucleotides from uridine nucleotides using soluble mammalian enzymes in 1960, requiring glutamine and GTP as cofactors. Subsequently, Charles W. Long and Arthur B. Pardee purified and kinetically analyzed CTP synthetase from Escherichia coli in 1967, establishing its glutamine-dependent amination of UTP to CTP and highlighting feedback inhibition by CTP itself.

Chemical structure

Molecular composition

Cytidine triphosphate (CTP) consists of three primary molecular components: the nitrogenous base cytosine, the pentose sugar β-D-ribofuranose, and a triphosphate moiety. Cytosine is a pyrimidine base characterized by a six-membered heterocyclic ring with nitrogens at positions 1 and 3, a keto group at C2, and an amino group at C4. The sugar component is ribose in its furanose form, a five-membered ring with hydroxyl groups at C2' and C3'. The triphosphate chain comprises three phosphate groups designated as α (closest to the sugar), β, and γ, each consisting of a phosphorus atom bonded to four oxygen atoms.^[10]^[11] The key linkages in CTP's structure include the N-glycosidic bond, which connects the N1 atom of the cytosine base to the C1' anomeric carbon of the ribose sugar. This bond is essential for integrating the base and sugar into the nucleoside unit. The triphosphate chain is attached to the ribose via a phosphoester bond between the 5'-oxygen of the ribose and the α-phosphate. Within the phosphate chain, the α and β phosphates, as well as the β and γ phosphates, are joined by high-energy phosphoanhydride bonds (P-O-P linkages), forming the characteristic linear triphosphate structure.^[10]^[11] Regarding stereochemistry, CTP exhibits a β configuration at the C1'-N1 glycosidic bond, positioning the cytosine base above the ribose ring plane in the standard anti conformation. The ribose sugar adopts the D-ribofuranose form with specific hydroxyl orientations: the 2'-OH and 3'-OH groups are in the cis (ribo) configuration relative to the CH2OPO3^2- at C4', distinguishing CTP from deoxyribonucleotide analogs lacking the 2'-OH. The phosphate chain is linear without branching, with the γ-phosphate at the terminus. The overall molecular formula of CTP is C9H16N3O14P3.^[10]^[11]

Physical and chemical properties

Cytidine triphosphate (CTP) is a white crystalline powder at room temperature, with a molecular weight of 483.21 g/mol.^[10]^[2] It exhibits high water solubility, approximately 11.2 g/L at neutral pH, owing to the polar phosphate groups, while being poorly soluble in organic solvents such as ether and chloroform.^[2]^[12] Chemically, CTP displays acid-base properties characteristic of nucleoside triphosphates, with pKa values of approximately 4.6 for the cytosine base protonation at N3 and 6.4 for the secondary ionization of the triphosphate chain.^[13] The primary phosphate pKa is around 0.9, similar to other NTPs. The phosphoanhydride bonds in the triphosphate moiety are susceptible to hydrolysis under acidic or alkaline conditions, releasing approximately -30 kJ/mol of free energy per bond cleaved, which contributes to its role as a high-energy compound.^[14]^[13] CTP demonstrates stability under neutral physiological conditions but is sensitive to enzymatic hydrolysis by phosphatases, which cleave the phosphate groups to form CDP or CMP.^[15] It absorbs ultraviolet light at 271 nm, attributable to the cytosine base, enabling spectrophotometric quantification.^[16]

Biosynthesis

De novo synthesis pathway

The de novo synthesis pathway of cytidine triphosphate (CTP) is integrated into the broader pyrimidine nucleotide biosynthesis route, commencing with the production of carbamoyl phosphate from glutamine, bicarbonate, and two ATP molecules, catalyzed by the enzyme carbamoyl phosphate synthetase II (CPSII) as part of the multifunctional CAD complex in eukaryotes.^[17] This initial step commits the pathway to pyrimidine production, distinct from the urea cycle's CPSI.^[17] Carbamoyl phosphate then reacts with aspartate in a condensation reaction facilitated by aspartate transcarbamoylase (ATCase), also within CAD, yielding N-carbamoylaspartate.^[17] This is followed by intramolecular cyclization to L-dihydroorotate, driven by dihydroorotase (DHOase), completing the CAD-mediated trifunctional segment of the pathway.^[17] Oxidation of L-dihydroorotate to orotate occurs via dihydroorotate dehydrogenase (DHODH), a flavin-dependent enzyme anchored to the mitochondrial inner membrane in eukaryotes, utilizing ubiquinone as an electron acceptor.^[18] Orotate subsequently combines with 5-phosphoribosyl-1-pyrophosphate (PRPP) through orotate phosphoribosyltransferase (OPRT) to form orotidine 5'-monophosphate (OMP), followed by decarboxylation of OMP to uridine monophosphate (UMP) by orotidine-5'-phosphate decarboxylase (ODC).^[17] In mammals, OPRT and ODC function as a bifunctional UMP synthase enzyme, ensuring efficient UMP production as the first pyrimidine nucleotide.^[17] UMP is phosphorylated to uridine diphosphate (UDP) by UMP-CMP kinase, which transfers a phosphate from ATP.^[19] UDP is then further phosphorylated to uridine triphosphate (UTP) by nucleoside diphosphate kinase (NDPK), again using ATP as the phosphate donor.^[19] The terminal step unique to CTP formation involves the amination of UTP, catalyzed by CTP synthetase (CTPS; EC 6.3.4.2^[20]), which incorporates an amino group from glutamine onto the 4-position of the uracil ring, powered by ATP hydrolysis.^[3] This rate-limiting reaction proceeds as follows:

\ce{UTP + glutamine + ATP + H2O -> CTP + glutamate + ADP + P_i}

In humans, CTPS exists as two isoforms, CTPS1 and CTPS2, which share high sequence similarity and contribute to de novo CTP production, with CTPS1 being particularly essential for immune cell proliferation.^[21] GTP serves as an allosteric activator, stimulating glutamine-dependent activity without being consumed.^[3] Overall, the de novo pathway to CTP is predominantly cytosolic in eukaryotic cells, with the exception of the mitochondrial DHODH step, facilitating coordinated nucleotide supply for cellular demands.^[22]

Salvage pathway

CTP can also be synthesized via salvage pathways that recycle free bases or nucleosides. Cytidine kinase phosphorylates exogenous cytidine to CMP, which is then converted to CDP and CTP by nucleoside monophosphate kinase and NDPK, respectively. Alternatively, cytosine phosphoribosyltransferase (UPRT acting on cytosine) forms CMP from cytosine and PRPP, followed by similar phosphorylation steps. These pathways provide an efficient means to maintain CTP levels under conditions of limited de novo synthesis or high nucleoside availability.^[1]

Regulation of biosynthesis

The biosynthesis of cytidine triphosphate (CTP) is tightly regulated to maintain cellular nucleotide pools and prevent imbalances that could disrupt nucleic acid synthesis and other metabolic processes. In mammalian cells, a primary mechanism of control is feedback inhibition at the pathway's initial enzyme, carbamoyl phosphate synthetase II (CPSII), which is allosterically inhibited by UTP, reducing the production of carbamoyl phosphate when pyrimidine levels are sufficient. CTP exerts its main feedback inhibition directly on CTP synthetase (CTPS), by binding to an allosteric site that promotes an inactive tetrameric state and suppresses glutamine hydrolysis.^[23]^[3] Allosteric regulation further fine-tunes CTPS activity in response to purine-pyrimidine balance. Guanosine triphosphate (GTP) serves as a positive allosteric effector, binding to the glutaminase domain of CTPS to enhance glutamine hydrolysis and ammonia transfer to the synthase domain, thereby activating the enzyme up to 50-fold in some systems. In contrast, CTP exerts inhibitory effects by competing with substrates and stabilizing inactive conformations. The GTP/CTP ratio critically modulates these interactions: high GTP levels promote CTPS filamentation, which can enhance activity in eukaryotes, while elevated CTP disrupts filaments and inhibits catalysis, linking purine availability to pyrimidine production.^[24]^[25]^[26] At the transcriptional level, CTPS genes are upregulated during cell proliferation to meet increased CTP demands for DNA and RNA synthesis. The oncogene Myc directly promotes the expression of CTPS1, the primary isoform contributing to CTP production in mammalian cells, particularly in rapidly dividing cells such as those in cancer or immune responses. CTPS2, while sharing similar functions, shows less pronounced Myc-dependent regulation but cooperates with CTPS1 in proliferating contexts. This transcriptional control integrates CTP biosynthesis with cell cycle progression, ensuring nucleotide availability scales with growth rates.^[27] The regulatory mechanisms involving CTPS filaments exhibit remarkable evolutionary conservation, facilitating metabolic channeling from bacteria to humans. CTPS self-assembles into filamentous structures, or cytoophidia, that spatially organize enzyme activity and ammonia transfer between active sites, preventing diffusion losses. In bacteria like Escherichia coli, filaments typically inhibit CTPS to conserve resources, whereas in eukaryotes including humans, they often enhance catalysis under substrate-rich conditions. This conserved polymerization, modulated by nucleotide ratios, underscores a fundamental strategy for coordinating nucleotide metabolism across kingdoms.^[28]

Biological roles

Role in nucleic acid synthesis

Cytidine triphosphate (CTP) serves as one of the four essential substrates for RNA polymerases in the transcription process, providing cytidylate (CMP) residues that are incorporated into the growing RNA chain through phosphodiester bond formation.^[29] During elongation, RNA polymerase catalyzes the addition of CTP opposite guanine bases in the DNA template, ensuring faithful replication of the genetic information into RNA molecules.^[22] This role is critical for the synthesis of all major RNA types, including messenger RNA (mRNA) for protein coding, transfer RNA (tRNA) for translation, and ribosomal RNA (rRNA) for ribosome assembly.^[30] In typical eukaryotic cells, cytidine residues constitute approximately 25% of the nucleotides in RNA, reflecting the average base composition and the need for balanced nucleotide pools to support efficient transcription.^[29] CTP levels are maintained in equilibrium with uridine triphosphate (UTP) through feedback regulation of CTP synthetase, which prevents imbalances that could lead to transcriptional errors or inefficiencies.^[25] Depletion of CTP, such as through inhibition of its synthesis, directly impairs RNA production by limiting substrate availability for RNA polymerase, halting elongation and reducing overall transcript yields.^[31] Although primarily involved in RNA synthesis, CTP indirectly supports DNA replication by serving as a precursor for deoxy-CTP (dCTP). CTP is converted to CDP, which is then reduced by ribonucleotide reductase to dCDP by removal of the 2'-hydroxyl group on the ribose sugar; dCDP is subsequently phosphorylated to dCTP by nucleoside diphosphate kinase.^[32]^[33] This conversion is tightly regulated to match cellular demands for DNA synthesis, with CTP's role in RNA remaining predominant under normal growth conditions.

Role in lipid metabolism

Cytidine triphosphate (CTP) serves as an essential activated donor in the Kennedy pathway, a major route for the de novo synthesis of glycerophospholipids in eukaryotic cells. In the phosphatidylcholine branch, choline is first phosphorylated to phosphocholine by choline kinase, after which CTP reacts with phosphocholine in a reaction catalyzed by CTP:phosphocholine cytidylyltransferase (CCT, also known as CTα in mammals) to form cytidine diphosphate-choline (CDP-choline) and pyrophosphate. This step activates the phosphocholine head group for subsequent transfer to diacylglycerol by choline/ethanolamine phosphotransferase (CEPT1) or choline phosphotransferase (CPT1), yielding phosphatidylcholine, the most abundant phospholipid in mammalian cell membranes.^[34]^[35] A parallel process occurs in the phosphatidylethanolamine branch of the Kennedy pathway, where ethanolamine is phosphorylated to phosphoethanolamine by ethanolamine kinase, followed by its cytidylylation with CTP via CTP:phosphoethanolamine cytidylyltransferase (ET, encoded by EPT1 in yeast or PCYT2 in mammals) to produce CDP-ethanolamine.^[36] CDP-ethanolamine then reacts with diacylglycerol, again catalyzed by CEPT1 or ethanolamine phosphotransferase (EPT1), to generate phosphatidylethanolamine, another key membrane lipid that contributes to bilayer curvature and fusion events.^[37]^[38] These reactions highlight CTP's role in providing the cytidylyl moiety, which facilitates the energy-efficient attachment of polar head groups to lipid backbones, thereby supporting the structural integrity and dynamics of cellular membranes.^[35] CTP also plays a pivotal role in the CDP-diacylglycerol (CDP-DAG) pathway for phospholipid synthesis. In this pathway, CTP reacts with phosphatidate, catalyzed by CDP-diacylglycerol synthase (CDS), to form CDP-DAG and pyrophosphate. CDP-DAG serves as the activated intermediate and lipid donor for the synthesis of several phospholipids, including phosphatidylserine (via phosphatidylserine synthase), phosphatidylinositol (via phosphatidylinositol synthase), phosphatidylglycerol (via phosphatidylglycerophosphate synthase), and cardiolipin (via cardiolipin synthase). These lipids are essential components of cellular membranes, particularly in mitochondria and the endoplasmic reticulum.^[39] The availability of CTP is tightly linked to lipid metabolism through CTP synthetase (CTPS), the enzyme that converts uridine triphosphate (UTP) to CTP using glutamine and ATP. In organisms such as the yeast Saccharomyces cerevisiae, CTPS isoforms (Ura7 and Ura8) are primary regulators of CTP pools, with Ura7 predominating; feedback inhibition by CTP and phosphorylation by protein kinase A or C modulate its activity to balance nucleotide demands with phospholipid production via the Kennedy pathway. This coordination is particularly critical during rapid cell proliferation, where increased membrane biogenesis requires elevated CTP levels to sustain phospholipid synthesis and prevent metabolic imbalances.^[40]^[41]

Role in glycosylation

CTP functions in the biosynthesis of sialoglycoconjugates by serving as a substrate for CMP-sialic acid synthetase (CMAS), which catalyzes the reaction of CTP with sialic acid (N-acetylneuraminic acid, Neu5Ac) to form cytidine monophosphate-sialic acid (CMP-Neu5Ac) and pyrophosphate. CMP-Neu5Ac is the activated donor used by sialyltransferases to add sialic acid residues to the terminal positions of N- and O-linked glycans on glycoproteins and glycolipids. This sialylation is crucial for various biological processes, including cell-cell recognition, immune modulation, pathogen binding, and protein stability. Dysregulation of sialylation is implicated in cancer progression and autoimmune diseases.^[42]^[43]

Regulatory functions

Cytidine triphosphate (CTP) serves as a key allosteric inhibitor of aspartate transcarbamoylase (ATCase), the enzyme catalyzing the committed step in de novo pyrimidine biosynthesis. By binding to the regulatory subunits of ATCase, CTP induces a conformational change that reduces the enzyme's affinity for aspartate, thereby decreasing the production of carbamoyl phosphate and subsequent pyrimidine nucleotides when CTP levels are elevated. This feedback mechanism is conserved across species, including in mammalian cells where ATCase forms part of the multifunctional CAD complex, preventing wasteful overaccumulation of pyrimidines.^[44]^[45] To maintain balance between purine and pyrimidine nucleotide pools, CTP's inhibitory effect on ATCase is counteracted by adenosine triphosphate (ATP), which acts as an allosteric activator. High ATP levels enhance ATCase activity, promoting pyrimidine synthesis when purine pools are abundant and ensuring coordinated nucleotide availability for DNA and RNA synthesis. Additionally, CTP contributes to pyrimidine homeostasis by participating in feedback regulation of downstream enzymes, such as inhibition of uridine-cytidine kinase in the salvage pathway alongside UTP, which limits excessive incorporation of exogenous pyrimidines.^[44]^[46] CTP also plays a role in cellular signaling by influencing nucleotide pool dynamics that affect the cell cycle. Fluctuations in CTP levels modulate the progression through S phase and mitosis, as balanced nucleotide pools are essential for DNA replication; depletion or imbalance disrupts proliferation. Furthermore, CTP synthetase (CTPS), the enzyme producing CTP, forms filamentous structures known as cytoophidia in response to high CTP concentrations, which allosterically inhibit its own activity and sense the metabolic state. These filaments assemble dynamically during periods of high proliferative demand, such as in rapidly dividing cells, linking nucleotide metabolism to cell cycle control.^[47]^[48]^[49] In certain pathways, CTP levels indirectly modulate protein kinase activities through interactions with metabolic sensors. For instance, CTPS filaments formed under high CTP conditions can influence the localization and activity of kinases like protein kinase A, which in turn phosphorylate CTPS to fine-tune its function, creating a regulatory loop that responds to nucleotide availability.^[50]^[51]

Metabolism and degradation

Catabolic pathways

The catabolic degradation of cytidine triphosphate (CTP) begins with stepwise dephosphorylation mediated by nonspecific phosphatases, converting CTP first to cytidine diphosphate (CDP) and then to cytidine monophosphate (CMP), releasing inorganic phosphate (Pi) at each step.^[52] Further dephosphorylation of CMP by 5'-nucleotidase yields cytidine and Pi.^[53] This process is irreversible under physiological conditions and occurs primarily in the liver, where excess nucleotides are recycled or eliminated to maintain cellular homeostasis.^[52] The nucleoside cytidine is then converted to uridine through deamination catalyzed by cytidine deaminase, which removes the amino group at the 4-position of the pyrimidine ring, producing ammonia (NH₃) as a byproduct.^[54] Uridine undergoes phosphorolysis via uridine phosphorylase (or pyrimidine nucleoside phosphorylase), cleaving the glycosidic bond to generate uracil and ribose 1-phosphate, the latter of which can enter other metabolic pathways such as the pentose phosphate pathway.^[52] The free base uracil is subsequently degraded through a reductive pathway involving dihydropyrimidine dehydrogenase, dihydropyrimidinase, and β-ureidopropionase, ultimately yielding β-alanine, CO₂, and additional NH₃.^[55] In mammals, the β-alanine produced can be reutilized in pantothenate synthesis or further metabolized to malonyl-CoA for fatty acid production, while CO₂ is excreted via respiration.^[52] In some organisms, such as certain bacteria and fungi, alternative oxidative or other reductive routes may lead to products like allantoate instead of β-alanine.^[56] The overall catabolism of CTP is distinct from reversible interconversions, such as to uridine triphosphate (UTP), which are covered elsewhere. Throughout dephosphorylation, the hydrolysis of the two high-energy phosphoanhydride bonds in CTP releases approximately 60 kJ/mol of free energy under standard conditions, contributing to cellular energy dissipation during nucleotide turnover.^[57]

Nucleotide interconversions

In the salvage pathway, cytidine, derived from nucleic acid degradation or dietary sources, is recycled into the nucleotide pool through sequential phosphorylation. Uridine-cytidine kinase (UCK) first catalyzes the phosphorylation of cytidine to cytidine monophosphate (CMP) using ATP as the phosphate donor.^[58] Subsequently, CMP kinase (CMPK), also known as UMP-CMP kinase, phosphorylates CMP to cytidine diphosphate (CDP).^[59] Finally, nucleoside diphosphate kinase (NDPK) transfers a phosphate group from ATP to CDP, yielding cytidine triphosphate (CTP).^[60] This multi-step salvage process allows cells to efficiently reutilize free cytidine, conserving energy compared to de novo synthesis. The production of deoxyribonucleotides from ribonucleotides involves reduction at the diphosphate level to generate precursors for DNA synthesis. Ribonucleotide reductase (RNR) catalyzes the conversion of CDP to 2'-deoxycytidine diphosphate (dCDP) in an allosterically regulated reaction that requires thioredoxin or glutaredoxin as a reducing system.^[32] dCDP is then phosphorylated by NDPK to form 2'-deoxycytidine triphosphate (dCTP), which serves as a substrate for DNA polymerases.^[60] This reduction step is tightly controlled to match cellular demands during the S phase of the cell cycle, preventing imbalances that could lead to mutagenesis. CTP and uridine triphosphate (UTP) undergo interconversion to maintain pyrimidine nucleotide homeostasis. In the forward direction, CTP synthetase irreversibly aminated UTP to CTP using glutamine as the nitrogen donor and ATP for energy, a key step that branches the pyrimidine pathway toward cytidine derivatives.^[61] The reverse interconversion occurs via deamination, where (d)CTP deaminase (CDADC1 in mammals) converts CTP back to UTP by hydrolytic removal of the 4-amino group.^[62] Although the deamination is not strictly reversible in the enzymatic sense, these bidirectional processes, often at the nucleoside or monophosphate levels in salvage contexts, allow flux between uridine and cytidine pools. These interconversion mechanisms collectively ensure balanced intracellular pools of CTP, UTP, and dCTP, supporting equitable demands for RNA transcription, DNA replication, and lipid biosynthesis. Dysregulation of salvage, reduction, or amination steps can disrupt this equilibrium, as seen in metabolic disorders where nucleotide imbalances affect cellular proliferation.^[63] By recycling precursors and adjusting synthesis rates, cells maintain physiological concentrations, typically in the micromolar range, to avoid toxicity from excess or deficiency.^[64]

Clinical and research significance

Associations with disease

Dysregulation of cytidine triphosphate (CTP) levels, primarily through alterations in CTP synthase 1 (CTPS1), has been implicated in various cancers, where overexpression promotes tumor cell proliferation by enhancing nucleotide availability for DNA and RNA synthesis. In acute myeloid leukemia (AML), elevated CTPS1 expression correlates with chemotherapy resistance, as it sustains pyrimidine pools necessary for rapid cell division, and its inhibition sensitizes cells to agents like cytarabine. Similarly, in lymphomas such as mantle cell lymphoma and T-cell neoplasms, CTPS1 upregulation drives oncogenic growth, with genetic or pharmacologic depletion reducing proliferation and enhancing sensitivity to therapies like venetoclax. Solid tumors, including those in the lung and breast, also exhibit CTPS1 overexpression, linking it to poor prognosis and metastatic potential through increased biosynthetic flux.^[65]^[66]^[67] Mutations in the CTPS1 gene cause immunodeficiency 24 (IMD24), a form of severe combined immunodeficiency (SCID) characterized by impaired T- and B-cell proliferation in response to antigenic stimulation, leading to recurrent bacterial, viral, and fungal infections. Homozygous hypomorphic mutations reduce CTPS1 enzymatic activity, limiting CTP production essential for lymphocyte expansion and differentiation, resulting in low naive T-cell counts and absent invariant natural killer T cells. Affected individuals often present with early-onset infections, including cytomegalovirus and Epstein-Barr virus, and require hematopoietic stem cell transplantation for survival.^[68]^[69]^[70] In neurodegenerative disorders like Alzheimer's disease, disruptions in pyrimidine metabolism contribute to pathology through altered CTP levels, which impair phospholipid turnover and neuronal membrane integrity. Deficits in mitochondrial respiratory complex IV activity, common in late-onset Alzheimer's, inhibit the de novo pyrimidine biosynthesis enzyme CAD, reducing CTP synthesis and subsequently lowering CDP-choline and phosphatidylcholine levels critical for synaptic function. This leads to decreased membrane phosphatide synthesis in brain regions like the hippocampus, exacerbating amyloid-beta accumulation and tau hyperphosphorylation. Studies in animal models show that supplementing uridine to boost CTP restores phospholipid levels and mitigates cognitive deficits, highlighting the pathway's role.^[71] Certain viruses exploit CTPS1 to facilitate replication by hijacking host CTP synthesis for viral nucleic acid production and immune evasion. For instance, SARS-CoV-2 upregulates CTPS1 to increase CTP pools, suppressing type I interferon responses and promoting viral genome replication in infected cells; inhibiting CTPS1 restores interferon induction and reduces viral loads in vitro and in animal models. This mechanism underscores CTPS1's vulnerability in viral infections, where elevated enzyme activity supports pathogen propagation at the expense of host antiviral defenses.^[72]

Therapeutic and research applications

Inhibitors of CTP synthetase (CTPS), the enzyme responsible for CTP biosynthesis, have emerged as promising chemotherapeutic agents by depleting CTP levels and disrupting nucleic acid synthesis in rapidly proliferating cancer cells. For instance, 6-diazo-5-oxo-L-norleucine (DON), a glutamine analog, inhibits CTPS activity, leading to suppressed cell proliferation and induction of apoptosis in lymphoma models. Similarly, acivicin, another glutamine-dependent inhibitor, targets CTPS and has demonstrated antiproliferative effects in B-cell lymphoma cell lines. As of 2025, the selective CTPS1 inhibitor STP938 is under investigation in a phase 1/2 clinical trial (NCT05463263) for relapsed/refractory B- and T-cell lymphomas, with ongoing recruitment to evaluate safety, tolerability, and preliminary efficacy.^[66]^[73]^[74]^[75] Cytidine diphosphate-choline (CDP-choline, also known as citicoline), a derivative related to CTP metabolism, is utilized as a neuroprotective supplement to support membrane repair and neuronal recovery in conditions such as stroke and traumatic brain injury (TBI). Clinical evidence from trials involving over 11,000 participants indicates that CDP-choline improves functional outcomes in acute ischemic stroke by enhancing phosphatidylcholine synthesis and reducing lipid peroxidation. In TBI management, it promotes neurorestoration, with studies showing benefits in cognitive and sensorimotor recovery during both acute and chronic phases. A 2025 meta-analysis confirmed its efficacy across various stroke trials, positioning it as a consistent neuroprotective agent without significant adverse effects.^[76]^[77]^[78]^[79] CTP analogs serve as antiviral agents by mimicking natural nucleotides and inhibiting viral RNA-dependent RNA polymerases, often acting as chain terminators during replication. For example, molnupiravir, a cytidine analog converted intracellularly to a CTP derivative, has shown broad-spectrum activity against SARS-CoV-2 by inducing mutagenic errors in viral genomes. Other analogs, such as 3'-deoxy-3',4'-didehydro-CTP (ddhCTP) produced by the host enzyme viperin, exhibit potent inhibition of diverse RNA viruses including flaviviruses and noroviruses. Remdesivir derivatives, while primarily adenosine-based, have inspired pyrimidine nucleotide analogs that compete directly with CTP pools to block polymerase activity in coronaviruses.^[80]^[81]^[82]^[83] Research on CTPS filament dynamics has advanced drug design by elucidating how these structures regulate enzyme activity and serve as potential therapeutic targets. Cryo-electron microscopy studies reveal that CTPS filaments form in response to CTP binding, stabilizing an inactive conformation that modulates biosynthesis under stress conditions, providing a structural basis for developing isoform-specific inhibitors. In 2025, high-resolution structures of human CTPS1 filaments bound to CTP have informed the design of targeted therapies for cancers and infections, highlighting opportunities to disrupt filament assembly for enhanced efficacy.^[28]^[84]^[85] CRISPR-based knockout studies of CTPS1 have underscored its essential role in cell proliferation, guiding applications in cancer research and synthetic lethality screens. Knockout of CTPS1, but not CTPS2, impairs proliferation in lymphoma and multiple myeloma cells by causing DNA damage and halting nucleotide synthesis, confirming its status as a vulnerability in high-renewal tissues. In MYC-driven cancers, CTPS1 inactivation synergizes with ATR inhibitors to induce synthetic lethality, reducing tumor growth without affecting normal cells. These findings from CRISPR screens have prioritized CTPS1 for therapeutic targeting in proliferative disorders like severe combined immunodeficiency (SCID), where brief mentions of etiological links highlight intervention potential.^[86]^[87]^[88]^[66]

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Cytidine triphosphate (CTP) is produced by ammonia addition of UTP catalyzed by CTP synthase. In animals, the amino group is provided by glutamine, while in ...
[15]
DHODH and cancer: promising prospects to be explored - PMC
May 10, 2021 · Dihydroorotate dehydrogenase (DHODH), located in the inner membrane of mitochondria, is an iron-containing flavin-dependent enzyme and plays a ...
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Purine and Pyrimidine Nucleotide Synthesis and Metabolism - PMC
Using 5-phosphoribosyl-1-pyrophosphate (PRPP), the de novo pathway enzymes build purine and pyrimidine nucleotides from “scratch” using simple molecules such as ...
[17]
CTP synthase 1 deficiency in humans reveals its central role in ...
The cytidine nucleotide triphosphate (CTP) is a precursor required for the metabolism of DNA, RNA and phospholipids. CTP originates from two sources: a ...
[18]
Characterization of filament-forming CTP synthases from ... - NIH
Long CW and Pardee AB (1967) Cytidine triphosphate synthetase of Escherichia coli B. I. Purification and kinetics. J. Biol. Chem 242, 4715–4721. [PubMed] ...
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From feedback inhibition to allostery: the enduring ... - FEBS Press
Aug 16, 2013 · ATCase is the first enzyme of the pyrimidine biosynthetic pathway, and is inhibited by CTP and UTP, the nucleotide end-products of the pathway.Missing: CTPS | Show results with:CTPS
[20]
Cytidine Triphosphate - an overview | ScienceDirect Topics
Cytidine triphosphate (CTP) is an allosteric inhibitor that plays a role in feedback inhibition in pyrimidine biosynthesis. It binds to the regulatory subunit ...Missing: nucleases | Show results with:nucleases
[21]
Common regulatory control of CTP synthase enzyme activity and ...
The E161K mutation decreases the affinity of the enzyme for CTP, which 1) negatively affects tetramerization (Long and Pardee, 1967; Pappas et al., 1998) and 2) ...
[22]
GTP-Dependent Regulation of CTP Synthase: Evolving Insights into ...
The NH3 generated from the hydrolysis of l-Gln is transferred to the synthase (amidoligase) domain via an intramolecular tunnel where it reacts with ...
[23]
Structural basis for ligand binding modes of CTP synthase - PNAS
Jul 23, 2021 · Cytidine triphosphate synthase (CTPS) catalyzes the final and rate-limiting step of de novo CTP biosynthesis, in which a UTP is converted into ...
[24]
Cytidine triphosphate synthase 1-mediated metabolic ...
Jul 15, 2024 · Upregulation of metabolism-related gene cytidine triphosphate synthase 1 (CTPS1) is associated with poor prognosis in multiple myeloma (MM).
[25]
Human CTP synthase filament structure reveals the active enzyme ...
Indeed, CTPS filaments co-localize with other metabolic and signaling enzymes, suggesting that cellular factors may specifically recognize and interact with ...
[26]
From DNA to RNA - Molecular Biology of the Cell - NCBI Bookshelf
Transcription and translation are the means by which cells read out, or express, the genetic instructions in their genes.
[27]
CTP synthase: the hissing of the cellular serpent - PMC
Jul 26, 2022 · CTP biosynthesis is carried out by two pathways: salvage and de novo. CTPsyn catalyzes the latter. The study of CTPsyn activity in mammalian ...
[28]
Identification of cytidine-5-triphosphate synthase1-selective ...
Jul 1, 2017 · Since CTP plays an important role in DNA/RNA synthesis, phospholipid synthesis, and protein sialyation, CTPS1-inhibition is expected to control ...
[29]
Ribonucleotide Reductases (RNRs): Structure, chemistry, and ...
Jun 25, 2020 · Ribonucleotide reductases (RNRs) catalyze the de novo conversion of nucleotides to deoxynucleotides in all organisms, controlling their relative ...
[30]
Activation of the anaerobic ribonucleotide reductase from ... - PubMed
Dec 15, 1992 · The anaerobic ribonucleoside triphosphate reductase from Escherichia coli reduces CTP to dCTP in the presence of a second protein, ...
[31]
Regulation of Human Cytidine Triphosphate Synthetase 2 by ...
Previous studies have shown that CTPS is regulated by tetramerization. CTPS can form a dimer of dimers, and the formation of tetramers by ATP and/or UTP ...Missing: phosphatases nucleases
[32]
https://pmc.ncbi.nlm.nih.gov/articles/PMC7316142/
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https://pubmed.ncbi.nlm.nih.gov/1460050/
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https://academic.oup.com/brain/article/142/11/3382/5601846
[37]
CTP synthetase and its role in phospholipid synthesis in the yeast ...
CTP synthetase is a cytosolic-associated glutamine amidotransferase enzyme that catalyzes the ATP-dependent transfer of the amide nitrogen from glutamine to ...Missing: functions | Show results with:functions
[38]
Allosteric Regulation of Catalytic Activity: Escherichia coli Aspartate ...
UTP can bind to the allosteric site, but inhibition of ATCase by UTP is possible only in combination with CTP. With CTP present, UTP binding is enhanced and ...
[39]
Full article: Inhibition of mammalian aspartate transcarbamylase by ...
ATCase in E. Coli has been shown to be subject to feedback inhibition by the pyrimidines specially cytosine nucleotides such as CDP, CTP, and dCTP which are the ...
[40]
The role of uridine-cytidine kinase in the regulation of pyrimidine ...
It is suggested that UTP and CTP act as feedback inhibitors of uridine—cytidine kinase. Such control of pyrimidine ribonucleotide synthesis may be of ...Missing: uridylate | Show results with:uridylate
[41]
Regulation of CTP Synthase Filament Formation During DNA ...
Therefore, CTPsyn monitors cellular nucleotide pools through its four NTP-binding sites, allowing it to match its activity to the concentration of nucleotides ( ...
[42]
Large-scale filament formation inhibits the activity of CTP synthetase
Jul 16, 2014 · By simultaneously monitoring CtpS polymerization and enzymatic activity, we show that polymerization inhibits activity, and CtpS's product, CTP, induces ...
[43]
Ack kinase regulates CTP synthase filaments during Drosophila ...
We demonstrate that CTPS filaments form transiently during oogenesis and are catalytically active and that their assembly is regulated by a novel filament ...
[44]
Dependence of protein kinase A activity on CTP synthetase...
CTP synthase is known to be regulated allosterically by ATP, UTP and CTP, through the protein kinases A [36] and C [50], and by the evolutionarily conserved ...Missing: modulation | Show results with:modulation
[45]
Phosphorylation of human CTP synthetase 1 by protein kinase A
CTP synthetase is an essential enzyme that generates the CTP required for the synthesis of nucleic acids and membrane phospholipids.Missing: modulation | Show results with:modulation
[46]
Nucleotide Metabolism - PMC - NIH
UMP generates UDP and UTP, which can generate CTP. Humans cannot break down the purine ring. The catabolism of purine nucleotides results in a uric acid. In ...
[47]
Purine and Pyrimidine Metabolism
Apr 12, 1997 · Purines consist of a six-membered and a five-membered nitrogen-containing ring, fused together. Pyridmidines have only a six-membered nitrogen-containing ring.
[48]
Physiologically based pharmacokinetic modelling of the three-step ...
Uracil, a pyrimidine base, is metabolized to β-alanine, ammonia and CO2 via three sequential reactions [1, 2] (Figure 1). Uracil is first reduced to ...
[49]
MetaCyc uracil degradation III - Trypanocyc
Pyrimidine nucleotides can be catabolized through three different pathways. The best characterized is the reductive pathway (see thymine degradation and uracil ...
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[PDF] lehninger-ch13_small.pdf
The Free Energy of Hydrolysis of ATP within Cells: The Real Cost of Doing Metabolic Business. The standard free energy of hydrolysis of ATP is. -30.5 kJ/mol ...
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Regulation of nucleotide metabolism in cancers and immune disorders
Uridine and cytidine can be recycled and phosphorylated by the enzyme uridine-cytidine kinase (UCK) to synthesize UMP and CMP, respectively. Additionally, the ...
[52]
Three Arabidopsis UMP kinases have different roles in pyrimidine ...
UMP phosphorylation to uridine diphosphate (UDP) by UMP KINASEs (UMKs) is required for the generation of all pyrimidine (deoxy)nucleoside triphosphates as ...
[53]
Saccharomyces cerevisiae nucleoside-diphosphate kinase - PubMed
Nucleoside-diphosphate kinase is an enzyme which catalyzes the phosphorylation of nucleoside diphosphates into the corresponding triphosphates for nucleic acid ...
[54]
A CTP Synthase Undergoing Stage-Specific Spatial Expression Is ...
Mar 22, 2018 · The synthesis of CTP by CTP synthase requires the substrates ATP, UTP and glutamine. GTP participates in the reaction as a positive effector ( ...
[55]
AID Mediates Hypermutation by Deaminating Single Stranded DNA
In contrast, cdd, a Bacillus subtilis cytidine deaminase (9), converted over 90% of CTP (or dCTP) to UTP (or dUTP) within minutes (online supplemental Fig. S1, ...
[56]
Nucleotide metabolism: a pan-cancer metabolic dependency - PMC
Mar 27, 2023 · The augmented synthesis and use of nucleotide triphosphates is a critical and universal metabolic dependency of cancer cells across different cancer types and ...
[57]
[PDF] Deoxyribonucleotides as Genetic and Metabolic Regulators
In the same study a dcd mutation, affecting dCTP deaminase, provoked transversion mutations by both G.C--->T.A and A.T--->T.A pathways (in E. coli the ...
[58]
Chemotherapy resistance in acute myeloid leukemia is mediated by ...
Oct 24, 2024 · Our observations revealed that A20 expression is elevated at diagnosis and contributes to diminished sensitivity of AML cells to chemotherapy.
[59]
CTP Synthase 1 Is a Novel Therapeutic Target in Lymphoma - PMC
Mar 28, 2023 · This report describes the identification and characterization of CTPS1 as a novel target in B- and T-cell cancers.
[60]
Selective pharmacologic targeting of CTPS1 shows single-agent ...
Feb 22, 2024 · Our study identified CTPS1 as a promising target for MCL patients and provided a mechanism-based combination with the BCL2 inhibitor venetoclax.Cell Culture · Transcriptomic Analysis · Results
[61]
CTP synthase 1 deficiency in humans reveals its central role in ...
Jun 12, 2014 · These results highlight a key and specific role of CTPS1 in the immune system by its capacity to sustain the proliferation of activated lymphocytes during the ...Missing: SCID original paper
[62]
Entry - #615897 - IMMUNODEFICIENCY 24; IMD24 - (OMIM.ORG)
A number sign (#) is used with this entry because of evidence that immunodeficiency-24 (IMD24) is caused by homozygous mutation in the CTPS1 gene (123860) on ...
[63]
Impaired lymphocyte function and differentiation in CTPS1-deficient ...
Mar 13, 2020 · In summary, CTPS1 deficiency is characterized by an almost complete absence of blood iNKT cell and MAIT cell subpopulations and decreased NK ...Missing: SCID | Show results with:SCID
[64]
Brain pyrimidine nucleotide synthesis and Alzheimer disease - PMC
Many patients suffering late-onset Alzheimer disease show a deficit in respiratory complex IV activity. The de novo pyrimidine biosynthesis pathway connects ...Missing: turnover | Show results with:turnover
[65]
Targeting CTP synthetase 1 to restore interferon induction and ...
Apr 29, 2025 · We report here that SARS-CoV-2 exploits cellular CTP synthetase 1 (CTPS1) to promote CTP synthesis and suppress interferon (IFN) induction.
[66]
CTP synthase: the hissing of the cellular serpent
Jul 26, 2022 · In mantle cell lymphoma (MCL), the oncogenic Myc was observed to be upregulated along with a significant upregulation of IMPDH2, CTPS1, and CAD, ...
[67]
Acivicin - an overview | ScienceDirect Topics
Moreover, compound 39 can effectively inhibit the proliferation of the P493B lymphoma cells. These studies provide an avenue for the development of a better ...
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Study Details | NCT05463263 | A Phase 1/2 Study of STP938 for Adult Subjects With Relapsed/Refractory B-Cell and T-Cell Lymphomas | ClinicalTrials.gov
- **Current Status (as of November 2025):** Recruiting
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Cytidine 5′-Diphosphocholine (CDP-Choline) in Stroke and Other ...
CDP-choline has been studied in >11,000 volunteers and patients and showed beneficial effects in cerebral ischemia, traumatic brain injury, hypoxia, Alzheimer's ...Missing: disodium | Show results with:disodium
[70]
Citicoline for the Management of Patients with Traumatic Brain Injury ...
Jan 29, 2023 · Citicoline or CDP-choline is a neuroprotective/neurorestorative drug used in several countries for the treatment of traumatic brain injury (TBI).Missing: triphosphate disodium
[71]
Neuroprotection and Recovery | Stroke
Dec 16, 2010 · Citicoline stimulates neuronal plasticity and improves sensorimotor recovery in the chronic phase of experimental stroke.Missing: disodium | Show results with:disodium
[72]
The efficacy of different doses of citicoline in improving ... - Frontiers
Apr 3, 2025 · CDP stands out as the sole medication that has consistently demonstrated neuroprotective effects across a variety of stroke clinical trials ( ...Missing: triphosphate disodium
[73]
2-thiouridine is a broad-spectrum antiviral nucleoside analogue ...
Molnupiravir is a cytidine analogue that exhibits antiviral activities against influenza virus (IFV), respiratory syncytial virus (RSV), and SARS-CoV-2 (14–16).Missing: examples | Show results with:examples<|separator|>
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Chemical Synthesis of the Antiviral Nucleotide Analogue ddhCTP
Jun 14, 2021 · Examples include i.v. administration of cidofovir for treatment of progressive multifocal leukoencephalopathy and Kaposi's sarcoma ...
[75]
Inhibition of SARS-CoV-2 polymerase by nucleotide analogs ... - eLife
Oct 7, 2021 · We characterize the impact of remdesivir (RDV, the only FDA-approved anti-coronavirus drug) and other nucleotide analogs (NAs) on RNA synthesis by the ...
[76]
Inhibition of SARS-CoV-2 polymerase by nucleotide analogs - bioRxiv
Apr 8, 2021 · In contrast, pyrimidine-based analogs, for example derivatives of CTP, will only need to compete with intracellular CTP pools on the order of ...
[77]
Cryo-EM structures of CTP synthase filaments reveal mechanism of ...
Nov 4, 2021 · Cryo-EM structures reveal a pH-sensitive assembly mechanism and highly ordered filament bundles that stabilize an inactive state of the enzyme.
[78]
Filamentation of hCTPS1 with CTP - Cell & Bioscience
Jul 30, 2025 · CTP synthase (CTPS) is a key enzyme in de novo CTP synthesis, playing a critical role in nucleotide metabolism and cellular proliferation.
[79]
Differential roles of CTP synthetases CTPS1 and CTPS2 in cell ...
Jun 22, 2023 · In humans, CTPS activity is dependent on two enzymes with highly conserved structural identity; the CTP synthases 1 and 2 (CTPS1 and CTPS2) that ...
[80]
Combined Inactivation of CTPS1 and ATR Is Synthetically Lethal to ...
Mar 15, 2022 · The “undruggable” oncogene MYC supports cancer cell proliferation and survival through parallel induction of multiple anabolic processes.
[81]
Inactivation of cytidine triphosphate synthase 1 prevents fatal auto ...
Mar 4, 2024 · However, both CTPS1 and CTPS2 are required for T cell proliferation following TCR stimulation. Deletion of Ctps1 in T cells or treatment with a ...Missing: Myc | Show results with:Myc