| CTPS1 | |||||||||||||||||||||||||||||||||||||||||||||||||||
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| Aliases | CTPS1 , CTPS, IMD24, CTP synthase 1, GATD5 | ||||||||||||||||||||||||||||||||||||||||||||||||||
| External IDs | OMIM: 123860 MGI: 1858304 HomoloGene: 20446 GeneCards: CTPS1 | ||||||||||||||||||||||||||||||||||||||||||||||||||
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CTP synthase 1 is an enzyme that is encoded by the CTPS1 gene in humans. [5] [6] CTP synthase 1 is an enzyme in the de novo pyrimidine synthesis pathway that catalyses the conversion of uridine triphosphate (UTP) to cytidine triphosphate (CTP). CTP is a key building block for the production of DNA, RNA and some phospholipids.
CTPS1 is an asymmetrical homotetramer with only three of its four monomers contributing to the catalytic domain. The substrates required for enzymatic activity are adenosine triphosphate (ATP), UTP and the amino acid glutamine. The ATP and UTP binding domains are located at the tetramer interface, whereas the glutamine binding domain is located away from the tetramer interface. [7]
Glutamine is hydrolysed by the glutamine amidotransferase domain on the outside of the CTPS1 enzyme. The ammonia produced is channelled through to the synthase domain in the interior of the enzyme, to the tetrameric interface. ATP-dependent phosphorylation of UTP produces 4-phosphoryl UTP, which reacts with the ammonia to produce CTP. The reaction can also take place using ammonia in solution in place of the glutamine-derived ammonia. Guanosine triphosphate (GTP) is an allosteric activator of enzyme activity which stimulates the hydrolysis of glutamine. CTP is an allosteric inhibitor of enzyme activity; the CTP binding site overlaps with and impedes the UTP binding site. Thus, CTPS1 enzymatic activity is sensitive to the levels of all four essential ribonucleotides. [8] [9]
The conversion of UTP to CTP is the final and rate limiting step in the de novo pyrimidine synthesis pathway. This step is unusual as it is catalysed by two homologous enzymes, CTPS1 and CTPS2, which share 74% homology at the protein level in humans. Human genetics suggest different cellular dependencies on CTPS1 and CTPS2 activity (see below).
Pyrimidines can also be generated by a salvage pathway that recycles DNA. Whilst the salvage pathway is sufficient for pyrimidine production in non-dividing cells, de novo pyrimidine synthesis is required for dividing cells.
Inherited CTPS1 deficiency is associated with a severe immunodeficiency syndrome characterised by life-threatening varicella zoster virus (VZV) and Epstein–Barr virus (EBV) infection in the first decade of life. Several cases of Epstein–Barr virus–associated lymphoproliferative disease have also been observed, including in the central nervous system. Importantly, no phenotype has been observed outside of the blood system, suggesting that CTPS2 is able to compensate for the CTPS1 loss in other tissues. [10] [11] [12]
All individuals described to date are homozygous for the same splicing mutation in CTPS1, which results in skipping of exon 18 resulting in a severely hypomorphic enzyme. All reported families have ancestry in the North West of England, indicating a founder effect for the causative mutation.
The blood systems of individuals with inherited CTPS1 deficiency are characterised by the following:
Inherited CTPS1 deficiency can be cured by allogeneic bone marrow transplantation. [13] [14]
Increased expression of CTPS1 has been reported to play a role in several different cancer types.
High expression of CTPS1 has been reported to impart a worse prognosis in myeloma, pancreatic cancer and breast cancer. [15] [16] [17] [18] [19] [20]
miR-125b-5p was identified as a tumour suppressor which is down regulated in squamous cell lung cancer; CTPS1 is a potential target of miR-125b-5p, and loss of expression of this miR is predicted to result in increased expression of CTPS1. [21]
CTPS1 knock down by shRNA inhibited tumour cell growth in a breast cancer model. [22] CTPS1 knock down by CRISPR showed synergy with inhibition of ATR in a model of MYC-driven cancer. [23]
The high proliferation rates and metabolic activity of cancer cells are likely to result in a critical dependency on the de novo pyrimidine synthesis pathway. This dependency is exploited therapeutically by several chemotherapy drugs that block de novo pyrimidine synthesis, including the nucleotide analogues cytosine arabinoside (ara-C) and gemcitabine. [24]
Cyclopentenyl cytosine (CPEC) is an inhibitor of both CTPS1 and CTPS2, with activity thought to be mediated by its 5'-triphosphate metabolite CPEC-TP. In phase 1 clinical studies, CPEC administration resulted in unpredictable and refractory hypotension, including fatal events, resulting in discontinuation of clinical development. [25] [26]
Recently, selective small molecule inhibitors have been described with a high degree of selectivity for CTPS1 over CTPS2. The binding mode and mechanism of CTPS1 selectivity has been resolved by cryo-EM which showed docking of the compounds to the CTP binding site of the enzyme. [27] A lead clinical candidate from this chemical series has shown efficacy in preclinical models of B and T cell neoplasia. [28]
A first in human clinical trial of a selective CTPS1 inhibitor will open to recruitment for patients with relapsed/refractory B cell lymphoma or T cell lymphoma late summer 2022 (NCT05463263). [29]
Nucleoside analogues have a long history in the treatment of viral infection. [30] [31]
Specific inhibition of CTP synthase has been identified as a target for anti-viral therapies. [32] [33]
Epstein–Barr virus (EBV) upregulates the expression of both CTPS1 and CTPS2 in infected B cells, with the expression of CTPS1 increasing earlier than CTPS2. The EBV protein ENBA-LP binds to the CTPS1 promoter, along with MYC and NFκB, to enhance expression of CTPS1. [34]
SARS-CoV-2, the virus that causes COVID-19, uses CTPS1 from infected cells to drive its proliferation; inhibition of CTPS1 has been highlighted as a potential anti-viral therapy. [35]
Nucleotides are organic molecules composed of a nitrogenous base, a pentose sugar and a phosphate. They serve as monomeric units of the nucleic acid polymers – deoxyribonucleic acid (DNA) and ribonucleic acid (RNA), both of which are essential biomolecules within all life-forms on Earth. Nucleotides are obtained in the diet and are also synthesized from common nutrients by the liver.
Uridine-5′-triphosphate (UTP) is a pyrimidine nucleoside triphosphate, consisting of the organic base uracil linked to the 1′ carbon of the ribose sugar, and esterified with tri-phosphoric acid at the 5′ position. Its main role is as substrate for the synthesis of RNA during transcription. UTP is the precursor for the production of CTP via CTP synthetase. UTP can be biosynthesized from UDP by Nucleoside Diphosphate Kinase after using the phosphate group from ATP. UDP + ATP ⇌ UTP + ADP; both UTP and ATP are energetically equal.
In biochemistry, a ribonucleotide is a nucleotide containing ribose as its pentose component. It is considered a molecular precursor of nucleic acids. Nucleotides are the basic building blocks of DNA and RNA. Ribonucleotides themselves are basic monomeric building blocks for RNA. Deoxyribonucleotides, formed by reducing ribonucleotides with the enzyme ribonucleotide reductase (RNR), are essential building blocks for DNA. There are several differences between DNA deoxyribonucleotides and RNA ribonucleotides. Successive nucleotides are linked together via phosphodiester bonds.
A salvage pathway is a pathway in which a biological product is produced from intermediates in the degradative pathway of its own or a similar substance. The term often refers to nucleotide salvage in particular, in which nucleotides are synthesized from intermediates in their degradative pathway.
A nucleoside triphosphate is a nucleoside containing a nitrogenous base bound to a 5-carbon sugar, with three phosphate groups bound to the sugar. They are the molecular precursors of both DNA and RNA, which are chains of nucleotides made through the processes of DNA replication and transcription. Nucleoside triphosphates also serve as a source of energy for cellular reactions and are involved in signalling pathways.
Nucleoside-diphosphate kinases are enzymes that catalyze the exchange of terminal phosphate between different nucleoside diphosphates (NDP) and triphosphates (NTP) in a reversible manner to produce nucleotide triphosphates. Many NDP serve as acceptor while NTP are donors of phosphate group. The general reaction via ping-pong mechanism is as follows: XDP + YTP ←→ XTP + YDP. NDPK activities maintain an equilibrium between the concentrations of different nucleoside triphosphates such as, for example, when guanosine triphosphate (GTP) produced in the citric acid (Krebs) cycle is converted to adenosine triphosphate (ATP). Other activities include cell proliferation, differentiation and development, signal transduction, G protein-coupled receptor, endocytosis, and gene expression.
Argininosuccinate synthase or synthetase is an enzyme that catalyzes the synthesis of argininosuccinate from citrulline and aspartate. In humans, argininosuccinate synthase is encoded by the ASS gene located on chromosome 9.
Purine nucleoside phosphorylase, PNP, PNPase or inosine phosphorylase is an enzyme that in humans is encoded by the NP gene. It catalyzes the chemical reaction
Nucleic acid metabolism is a collective term that refers to the variety of chemical reactions by which nucleic acids are either synthesized or degraded. Nucleic acids are polymers made up of a variety of monomers called nucleotides. Nucleotide synthesis is an anabolic mechanism generally involving the chemical reaction of phosphate, pentose sugar, and a nitrogenous base. Degradation of nucleic acids is a catabolic reaction and the resulting parts of the nucleotides or nucleobases can be salvaged to recreate new nucleotides. Both synthesis and degradation reactions require multiple enzymes to facilitate the event. Defects or deficiencies in these enzymes can lead to a variety of diseases.
CAD protein is a trifunctional multi-domain enzyme involved in the first three steps of pyrimidine biosynthesis. De-novo synthesis starts with cytosolic carbamoylphosphate synthetase II which uses glutamine, carbon dioxide and ATP. This enzyme is inhibited by uridine triphosphate.
CTP synthase is an enzyme involved in pyrimidine biosynthesis that interconverts UTP and CTP.
Orotate phosphoribosyltransferase (OPRTase) or orotic acid phosphoribosyltransferase is an enzyme involved in pyrimidine biosynthesis. It catalyzes the formation of orotidine 5'-monophosphate (OMP) from orotate and phosphoribosyl pyrophosphate. In yeast and bacteria, orotate phosphoribosyltransferase is an independent enzyme with a unique gene coding for the protein, whereas in mammals and other multicellular organisms, the catalytic function is carried out by a domain of the bifunctional enzyme UMP synthase (UMPS).
Purine metabolism refers to the metabolic pathways to synthesize and break down purines that are present in many organisms.
Deoxycytidine kinase (dCK) is an enzyme which is encoded by the DCK gene in humans. dCK predominantly phosphorylates deoxycytidine (dC) and converts dC into deoxycytidine monophosphate. dCK catalyzes one of the initial steps in the nucleoside salvage pathway and has the potential to phosphorylate other preformed nucleosides, specifically deoxyadenosine (dA) and deoxyguanosine (dG), and convert them into their monophosphate forms. There has been recent biomedical research interest in investigating dCK's potential as a therapeutic target for different types of cancer.
Phosphatidate cytidylyltransferase (CDS) is the enzyme that catalyzes the synthesis of CDP-diacylglycerol from cytidine triphosphate and phosphatidate.
Cytidine deaminase is an enzyme that in humans is encoded by the CDA gene.
Cytosolic 5'-nucleotidase 3 (NTC53), also known as cytosolic 5'-nucleotidase 3A, pyrimidine 5’-nucleotidase, and p56, is an enzyme that in humans is encoded by the NT5C3, or NT5C3A, gene on chromosome 7.
Uridine-cytidine kinase 2 (UCK2) is an enzyme that in humans is encoded by the UCK2 gene.
Bifunctional 3'-phosphoadenosine 5'-phosphosulfate synthetase 1 is an enzyme that in humans is encoded by the PAPSS1 gene.
CTP synthase 2 is an enzyme that in humans is encoded by the CTPS2 gene.
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This article incorporates text from the United States National Library of Medicine, which is in the public domain.
