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CTP synthase 1

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CTPS1
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesCTPS1, CTPS, IMD24, CTP synthase 1, GATD5
External IDsOMIM: 123860; MGI: 1858304; HomoloGene: 20446; GeneCards: CTPS1; OMA:CTPS1 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

1503

51797

Ensembl

ENSG00000171793

ENSMUSG00000028633

UniProt

P17812

P70698

RefSeq (mRNA)

NM_001301237
NM_001905

NM_016748
NM_001355491

RefSeq (protein)

NP_001288166
NP_001896

NP_058028
NP_001342420

Location (UCSC)Chr 1: 40.98 – 41.01 MbChr 4: 120.4 – 120.43 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

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.

Structure and function

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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]

De novo pyrimidine synthesis pathway

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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.

Clinical significance

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Inherited mutations

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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:

  1. Normal numbers of T cells, normal T cell subsets
  2. Near absence of invariant NKT cells and mucosal associated invariant T cell
  3. Normal numbers of total B cells, reduced proportion of memory B cells
  4. Reduced numbers of NK cells
  5. Severely impaired T cell proliferation response and reduced IL-2 secretion following activation
  6. Impaired B cell proliferation response following activation
  7. Elevated IgG with selective deficiencies of specific antibodies
  8. Normal numbers and subset distribution of myeloid cells and dendritic cells

Inherited CTPS1 deficiency can be cured by allogeneic bone marrow transplantation.[13][14]

Cancer

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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]

CTPS1 as a therapeutic target

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Cancer therapy

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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]

Anti-viral therapy

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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]

References

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  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000171793 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000028633 – Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ Yamauchi M, Yamauchi N, Phear G, Spurr NK, Martinsson T, Weith A, et al. (December 1991). "Genomic organization and chromosomal localization of the human CTP synthetase gene (CTPS)". Genomics. 11 (4): 1088–1096. doi:10.1016/0888-7543(91)90036-E. PMID 1783378.
  6. ^ "Entrez Gene: CTP synthase".
  7. ^ Kursula P, Flodin S, Ehn M, Hammarström M, Schüler H, Nordlund P, et al. (July 2006). "Structure of the synthetase domain of human CTP synthetase, a target for anticancer therapy". Acta Crystallographica. Section F, Structural Biology and Crystallization Communications. 62 (Pt 7): 613–617. doi:10.1107/S1744309106018136. PMC 2242944. PMID 16820675.
  8. ^ Lauritsen I, Willemoës M, Jensen KF, Johansson E, Harris P (February 2011). "Structure of the dimeric form of CTP synthase from Sulfolobus solfataricus". Acta Crystallographica. Section F, Structural Biology and Crystallization Communications. 67 (Pt 2): 201–208. doi:10.1107/S1744309110052334. PMC 3034608. PMID 21301086.
  9. ^ Lynch EM, Kollman JM (January 2020). "Coupled structural transitions enable highly cooperative regulation of human CTPS2 filaments". Nature Structural & Molecular Biology. 27 (1): 42–48. doi:10.1038/s41594-019-0352-5. PMC 6954954. PMID 31873303.
  10. ^ Martin E, Palmic N, Sanquer S, Lenoir C, Hauck F, Mongellaz C, et al. (June 2014). "CTP synthase 1 deficiency in humans reveals its central role in lymphocyte proliferation". Nature. 510 (7504): 288–292. Bibcode:2014Natur.510..288M. doi:10.1038/nature13386. PMC 6485470. PMID 24870241.
  11. ^ Martin E, Minet N, Boschat AC, Sanquer S, Sobrino S, Lenoir C, et al. (March 2020). "Impaired lymphocyte function and differentiation in CTPS1-deficient patients result from a hypomorphic homozygous mutation". JCI Insight. 5 (5): 133880. doi:10.1172/jci.insight.133880. PMC 7141395. PMID 32161190.
  12. ^ Nademi Z, Wynn RF, Slatter M, Hughes SM, Bonney D, Qasim W, et al. (January 2019). "Hematopoietic stem cell transplantation for cytidine triphosphate synthase 1 (CTPS1) deficiency" (PDF). Bone Marrow Transplantation. 54 (1): 130–133. doi:10.1038/s41409-018-0246-x. PMID 29884857. S2CID 46999914.
  13. ^ Nademi Z, Wynn RF, Slatter M, Hughes SM, Bonney D, Qasim W, et al. (January 2019). "Hematopoietic stem cell transplantation for cytidine triphosphate synthase 1 (CTPS1) deficiency" (PDF). Bone Marrow Transplantation. 54 (1): 130–133. doi:10.1038/s41409-018-0246-x. PMID 29884857. S2CID 46999914.
  14. ^ Kucuk ZY, Zhang K, Filipovich L, Bleesing JJ (November 2016). "CTP Synthase 1 Deficiency in Successfully Transplanted Siblings with Combined Immune Deficiency and Chronic Active EBV Infection". Journal of Clinical Immunology. 36 (8): 750–753. doi:10.1007/s10875-016-0332-z. PMID 27638562. S2CID 44209317.
  15. ^ Huang HY, Wang Y, Wang WD, Wei XL, Gale RP, Li JY, et al. (November 2021). "A prognostic survival model based on metabolism-related gene expression in plasma cell myeloma". Leukemia. 35 (11): 3212–3222. doi:10.1038/s41375-021-01206-4. PMID 33686197. S2CID 232137095.
  16. ^ Shukla SK, Purohit V, Mehla K, Gunda V, Chaika NV, Vernucci E, et al. (July 2017). "MUC1 and HIF-1alpha Signaling Crosstalk Induces Anabolic Glucose Metabolism to Impart Gemcitabine Resistance to Pancreatic Cancer". Cancer Cell. 32 (1): 71–87.e7. doi:10.1016/j.ccell.2017.06.004. PMC 5533091. PMID 28697344.
  17. ^ Conte F, Sibilio P, Grimaldi AM, Salvatore M, Paci P, Incoronato M (2022). "In silico recognition of a prognostic signature in basal-like breast cancer patients". PLOS ONE. 17 (2): e0264024. Bibcode:2022PLoSO..1764024C. doi:10.1371/journal.pone.0264024. PMC 8846521. PMID 35167614.
  18. ^ Lin Y, Zhang J, Li Y, Guo W, Chen L, Chen M, et al. (January 2022). "CTPS1 promotes malignant progression of triple-negative breast cancer with transcriptional activation by YBX1". Journal of Translational Medicine. 20 (1): 17. doi:10.1186/s12967-021-03206-5. PMC 8734240. PMID 34991621.
  19. ^ Cao W, Jiang Y, Ji X, Guan X, Lin Q, Ma L (February 2021). "Identification of novel prognostic genes of triple-negative breast cancer using meta-analysis and weighted gene co-expressed network analysis". Annals of Translational Medicine. 9 (3): 205. doi:10.21037/atm-20-5989. PMC 7940929. PMID 33708832.
  20. ^ Huang SP, Jiang YF, Yang LJ, Yang J, Liang MT, Zhou HF, et al. (March 2022). "Downregulation of miR-125b-5p and Its Prospective Molecular Mechanism in Lung Squamous Cell Carcinoma". Cancer Biotherapy & Radiopharmaceuticals. 37 (2): 125–140. doi:10.1089/cbr.2020.3657. PMID 32614608. S2CID 220327036.
  21. ^ Huang SP, Jiang YF, Yang LJ, Yang J, Liang MT, Zhou HF, et al. (March 2022). "Downregulation of miR-125b-5p and Its Prospective Molecular Mechanism in Lung Squamous Cell Carcinoma". Cancer Biotherapy & Radiopharmaceuticals. 37 (2): 125–140. doi:10.1089/cbr.2020.3657. PMID 32614608. S2CID 220327036.
  22. ^ Lin Y, Zhang J, Li Y, Guo W, Chen L, Chen M, et al. (January 2022). "CTPS1 promotes malignant progression of triple-negative breast cancer with transcriptional activation by YBX1". Journal of Translational Medicine. 20 (1): 17. doi:10.1186/s12967-021-03206-5. PMC 8734240. PMID 34991621.
  23. ^ Sun Z, Zhang Z, Wang QQ, Liu JL (March 2022). "Combined Inactivation of CTPS1 and ATR Is Synthetically Lethal to MYC-Overexpressing Cancer Cells". Cancer Research. 82 (6): 1013–1024. doi:10.1158/0008-5472.CAN-21-1707. PMC 9359733. PMID 35022212.
  24. ^ Jordheim LP, Durantel D, Zoulim F, Dumontet C (June 2013). "Advances in the development of nucleoside and nucleotide analogues for cancer and viral diseases". Nature Reviews. Drug Discovery. 12 (6): 447–464. doi:10.1038/nrd4010. ISSN 1474-1784. PMID 23722347. S2CID 39842610.
  25. ^ Schimmel KJ, Gelderblom H, Guchelaar HJ (August 2007). "Cyclopentenyl cytosine (CPEC): an overview of its in vitro and in vivo activity". Current Cancer Drug Targets. 7 (5): 504–509. doi:10.2174/156800907781386579. PMID 17691910.
  26. ^ Politi PM, Xie F, Dahut W, Ford H, Kelley JA, Bastian A, et al. (1995). "Phase I clinical trial of continuous infusion cyclopentenyl cytosine". Cancer Chemotherapy and Pharmacology. 36 (6): 513–523. doi:10.1007/BF00685802. PMID 7554044. S2CID 799892.
  27. ^ Lynch EM, DiMattia MA, Albanese S, van Zundert GC, Hansen JM, Quispe JD, et al. (October 2021). "Structural basis for isoform-specific inhibition of human CTPS1". Proceedings of the National Academy of Sciences of the United States of America. 118 (40): e2107968118. Bibcode:2021PNAS..11807968L. doi:10.1073/pnas.2107968118. PMC 8501788. PMID 34583994.
  28. ^ Asnagli H, Minet N, Pfeiffer C, Hoeben E, Lane R, Laughton D, et al. (April 2023). "CTP Synthase 1 Is a Novel Therapeutic Target in Lymphoma". HemaSphere. 7 (4): e864. doi:10.1097/HS9.0000000000000864. PMC 10060080. PMID 37008165.
  29. ^ Clinical trial number NCT05463263 for "An Open-Label, First in Human, Phase 1/2 to Evaluate Safety, Tolerability, Pharmacokinetics, and Preliminary Efficacy of the CTPS1 Inhibitor STP938 In Adult Subjects With Relapsed/Refractory B-Cell and T-Cell Lymphomas" at ClinicalTrials.gov
  30. ^ De Clercq E (1994-07-01). "Antiviral Activity Spectrum and Target of Action of Different Classes of Nucleoside Analogues". Nucleosides and Nucleotides. 13 (6–7): 1271–1295. doi:10.1080/15257779408012151. ISSN 0732-8311.
  31. ^ Jordheim LP, Durantel D, Zoulim F, Dumontet C (June 2013). "Advances in the development of nucleoside and nucleotide analogues for cancer and viral diseases". Nature Reviews. Drug Discovery. 12 (6): 447–464. doi:10.1038/nrd4010. PMID 23722347. S2CID 39842610.
  32. ^ De Clercq E, Bernaerts R, Shealy YF, Montgomery JA (January 1990). "Broad-spectrum antiviral activity of carbodine, the carbocyclic analogue of cytidine". Biochemical Pharmacology. 39 (2): 319–325. doi:10.1016/0006-2952(90)90031-f. PMC 7111205. PMID 1689159.
  33. ^ De Clercq E, Murase J, Marquez VE (June 1991). "Broad-spectrum antiviral and cytocidal activity of cyclopentenylcytosine, a carbocyclic nucleoside targeted at CTP synthetase". Biochemical Pharmacology. 41 (12): 1821–1829. doi:10.1016/0006-2952(91)90120-t. PMC 7111160. PMID 1710119.
  34. ^ Liang JH, Wang C, Yiu SP, Zhao B, Guo R, Gewurz BE (August 2021). "Epstein-Barr Virus Induced Cytidine Metabolism Roles in Transformed B-Cell Growth and Survival". mBio. 12 (4): e0153021. doi:10.1128/mBio.01530-21. PMC 8406234. PMID 34281398.
  35. ^ Rao Y, Wang TY, Qin C, Espinosa B, Liu Q, Ekanayake A, et al. (February 2021). "Targeting CTP Synthetase 1 to Restore Interferon Induction and Impede Nucleotide Synthesis in SARS-CoV-2 Infection". bioRxiv: 2021.02.05.429959. doi:10.1101/2021.02.05.429959. PMC 7872357. PMID 33564769.

Further reading

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This article incorporates text from the United States National Library of Medicine, which is in the public domain.

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