Target Information
| Target General Information | Top | |||||
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| Target ID |
T70101
(Former ID: TTDR00956)
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| Target Name |
CTP synthase (CTPS1)
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| Synonyms |
Uridine triphosphate aminase; UTP:ammonia ligase (ADP-forming); UTP--ammonia ligase; Cytidine triphosphate synthetase; Cytidine 5'-triphosphate synthetase; CTPS1; CTP synthetase
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| Gene Name |
CTPS1
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| Target Type |
Clinical trial target
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[1] | ||||
| Disease | [+] 1 Target-related Diseases | + | ||||
| 1 | Solid tumour/cancer [ICD-11: 2A00-2F9Z] | |||||
| Function |
This enzyme is involved in the de novo synthesis of CTP, a precursor of DNA, RNA and phospholipids. Catalyzes the ATP- dependent amination of UTP to CTP with either L-glutamine or ammonia as a source of nitrogen. This enzyme and its product, CTP, play a crucial role in the proliferation of activated lymphocytes and therefore in immunity.
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| BioChemical Class |
Carbon-nitrogen ligase
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| UniProt ID | ||||||
| EC Number |
EC 6.3.4.2
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| Sequence |
MKYILVTGGVISGIGKGIIASSVGTILKSCGLHVTSIKIDPYINIDAGTFSPYEHGEVFV
LDDGGEVDLDLGNYERFLDIRLTKDNNLTTGKIYQYVINKERKGDYLGKTVQVVPHITDA IQEWVMRQALIPVDEDGLEPQVCVIELGGTVGDIESMPFIEAFRQFQFKVKRENFCNIHV SLVPQPSSTGEQKTKPTQNSVRELRGLGLSPDLVVCRCSNPLDTSVKEKISMFCHVEPEQ VICVHDVSSIYRVPLLLEEQGVVDYFLRRLDLPIERQPRKMLMKWKEMADRYDRLLETCS IALVGKYTKFSDSYASVIKALEHSALAINHKLEIKYIDSADLEPITSQEEPVRYHEAWQK LCSAHGVLVPGGFGVRGTEGKIQAIAWARNQKKPFLGVCLGMQLAVVEFSRNVLGWQDAN STEFDPTTSHPVVVDMPEHNPGQMGGTMRLGKRRTLFQTKNSVMRKLYGDADYLEERHRH RFEVNPVWKKCLEEQGLKFVGQDVEGERMEIVELEDHPFFVGVQYHPEFLSRPIKPSPPY FGLLLASVGRLSHYLQKGCRLSPRDTYSDRSGSSSPDSEITELKFPSINHD Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | PDB | ||||
| Drugs and Modes of Action | Top | |||||
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| Clinical Trial Drug(s) | [+] 1 Clinical Trial Drugs | + | ||||
| 1 | Cyclopentenylcytosine | Drug Info | Phase 1 | Solid tumour/cancer | [2] | |
| Mode of Action | [+] 1 Modes of Action | + | ||||
| Inhibitor | [+] 6 Inhibitor drugs | + | ||||
| 1 | Cyclopentenylcytosine | Drug Info | [1] | |||
| 2 | Acivicin | Drug Info | [3], [4] | |||
| 3 | 2-Methyl-2,4-Pentanediol | Drug Info | [5] | |||
| 4 | Carbodine | Drug Info | [6] | |||
| 5 | Cyclopentylcytosine | Drug Info | [1] | |||
| 6 | Cylopentenyl cytosine | Drug Info | [7] | |||
| Cell-based Target Expression Variations | Top | |||||
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| Cell-based Target Expression Variations | ||||||
| Drug Binding Sites of Target | Top | |||||
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| Ligand Name: L-glutamine | Ligand Info | |||||
| Structure Description | Human CTPS1 bound to UTP, AMPPNP, and glutamine | PDB:7MGZ | ||||
| Method | Electron microscopy | Resolution | 2.80 Å | Mutation | No | [8] |
| PDB Sequence |
MKYILVTGGV
10 ISGIGKGIIA20 SSVGTILKSC30 GLHVTSIKID40 PYINIDAGTF50 SPYEHGEVFV 60 LDDGGEVDLD70 LGNYERFLDI80 RLTKDNNLTT90 GKIYQYVINK100 ERKGDYLGKT 110 VQVVPHITDA120 IQEWVMRQAL130 IPVDEDGLEP140 QVCVIELGGT150 VGDIESMPFI 160 EAFRQFQFKV170 KRENFCNIHV180 SLVPQPSSTG190 EQKTKPTQNS200 VRELRGLGLS 210 PDLVVCRCSN220 PLDTSVKEKI230 SMFCHVEPEQ240 VICVHDVSSI250 YRVPLLLEEQ 260 GVVDYFLRRL270 DLPKMLMKWK286 EMADRYDRLL296 ETCSIALVGK306 YTKFSDSYAS 316 VIKALEHSAL326 AINHKLEIKY336 IDSADLEPIT346 SQEEPVRYHE356 AWQKLCSAHG 366 VLVPGGFGVR376 GTEGKIQAIA386 WARNQKKPFL396 GVCLGMQLAV406 VEFSRNVLGW 416 QDANSTEFDP426 TTSHPVVVDM436 PEHNMRLGKR453 RTLFQTKNSV463 MRKLYGDADY 473 LEERHRHRFE483 VNPVWKKCLE493 EQGLKFVGQD503 VEGERMEIVE513 LEDHPFFVGV 523 QYHPEFLSRP533 IKPSPPYFGL543 LLASVGRLSH553 YL
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| Click to View More Binding Site Information of This Target and Ligand Pair | ||||||
| Ligand Name: AMP-PNP | Ligand Info | |||||
| Structure Description | Human CTPS1 bound to UTP, AMPPNP, and glutamine | PDB:7MGZ | ||||
| Method | Electron microscopy | Resolution | 2.80 Å | Mutation | No | [8] |
| PDB Sequence |
MKYILVTGGV
10 ISGIGKGIIA20 SSVGTILKSC30 GLHVTSIKID40 PYINIDAGTF50 SPYEHGEVFV 60 LDDGGEVDLD70 LGNYERFLDI80 RLTKDNNLTT90 GKIYQYVINK100 ERKGDYLGKT 110 VQVVPHITDA120 IQEWVMRQAL130 IPVDEDGLEP140 QVCVIELGGT150 VGDIESMPFI 160 EAFRQFQFKV170 KRENFCNIHV180 SLVPQPSSTG190 EQKTKPTQNS200 VRELRGLGLS 210 PDLVVCRCSN220 PLDTSVKEKI230 SMFCHVEPEQ240 VICVHDVSSI250 YRVPLLLEEQ 260 GVVDYFLRRL270 DLPKMLMKWK286 EMADRYDRLL296 ETCSIALVGK306 YTKFSDSYAS 316 VIKALEHSAL326 AINHKLEIKY336 IDSADLEPIT346 SQEEPVRYHE356 AWQKLCSAHG 366 VLVPGGFGVR376 GTEGKIQAIA386 WARNQKKPFL396 GVCLGMQLAV406 VEFSRNVLGW 416 QDANSTEFDP426 TTSHPVVVDM436 PEHNMRLGKR453 RTLFQTKNSV463 MRKLYGDADY 473 LEERHRHRFE483 VNPVWKKCLE493 EQGLKFVGQD503 VEGERMEIVE513 LEDHPFFVGV 523 QYHPEFLSRP533 IKPSPPYFGL543 LLASVGRLSH553 YL
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SER12
3.003
GLY13
2.105
ILE14
2.121
GLY15
2.272
LYS16
1.787
GLY17
1.601
ILE18
2.391
ILE19
4.129
LYS38
2.185
HIS55
4.016
ASP68
3.868
LEU69
3.850
ASP70
3.271
ASN73
3.936
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| Click to View More Binding Site Information of This Target with Different Ligands | ||||||
| Different Human System Profiles of Target | Top |
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Human Similarity Proteins
of target is determined by comparing the sequence similarity of all human proteins with the target based on BLAST. The similarity proteins for a target are defined as the proteins with E-value < 0.005 and outside the protein families of the target.
A target that has fewer human similarity proteins outside its family is commonly regarded to possess a greater capacity to avoid undesired interactions and thus increase the possibility of finding successful drugs
(Brief Bioinform, 21: 649-662, 2020).
Human Tissue Distribution
of target is determined from a proteomics study that quantified more than 12,000 genes across 32 normal human tissues. Tissue Specificity (TS) score was used to define the enrichment of target across tissues.
The distribution of targets among different tissues or organs need to be taken into consideration when assessing the target druggability, as it is generally accepted that the wider the target distribution, the greater the concern over potential adverse effects
(Nat Rev Drug Discov, 20: 64-81, 2021).
Human Pathway Affiliation
of target is determined by the life-essential pathways provided on KEGG database. The target-affiliated pathways were defined based on the following two criteria (a) the pathways of the studied target should be life-essential for both healthy individuals and patients, and (b) the studied target should occupy an upstream position in the pathways and therefore had the ability to regulate biological function.
Targets involved in a fewer pathways have greater likelihood to be successfully developed, while those associated with more human pathways increase the chance of undesirable interferences with other human processes
(Pharmacol Rev, 58: 259-279, 2006).
Biological Network Descriptors
of target is determined based on a human protein-protein interactions (PPI) network consisting of 9,309 proteins and 52,713 PPIs, which were with a high confidence score of ≥ 0.95 collected from STRING database.
The network properties of targets based on protein-protein interactions (PPIs) have been widely adopted for the assessment of target’s druggability. Proteins with high node degree tend to have a high impact on network function through multiple interactions, while proteins with high betweenness centrality are regarded to be central for communication in interaction networks and regulate the flow of signaling information
(Front Pharmacol, 9, 1245, 2018;
Curr Opin Struct Biol. 44:134-142, 2017).
Human Similarity Proteins
Human Tissue Distribution
Human Pathway Affiliation
Biological Network Descriptors
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There is no similarity protein (E value < 0.005) for this target
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Note:
If a protein has TS (tissue specficity) scores at least in one tissue >= 2.5, this protein is called tissue-enriched (including tissue-enriched-but-not-specific and tissue-specific). In the plots, the vertical lines are at thresholds 2.5 and 4.
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| KEGG Pathway | Pathway ID | Affiliated Target | Pathway Map |
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| Pyrimidine metabolism | hsa00240 | Affiliated Target |
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| Class: Metabolism => Nucleotide metabolism | Pathway Hierarchy | ||
| Degree | 2 | Degree centrality | 2.15E-04 | Betweenness centrality | 0.00E+00 |
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| Closeness centrality | 1.66E-01 | Radiality | 1.25E+01 | Clustering coefficient | 1.00E+00 |
| Neighborhood connectivity | 9.00E+00 | Topological coefficient | 6.00E-01 | Eccentricity | 13 |
| Download | Click to Download the Full PPI Network of This Target | ||||
| Drug Property Profile of Target | Top | |
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| (1) Molecular Weight (mw) based Drug Clustering | (2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering | |
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| (3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering | (4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering | |
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| (5) Rotatable Bond Count (rotbonds) based Drug Clustering | (6) Topological Polar Surface Area (polararea) based Drug Clustering | |
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| "RO5" indicates the cutoff set by lipinski's rule of five; "D123AB" colored in GREEN denotes the no violation of any cutoff in lipinski's rule of five; "D123AB" colored in PURPLE refers to the violation of only one cutoff in lipinski's rule of five; "D123AB" colored in BLACK represents the violation of more than one cutoffs in lipinski's rule of five | ||
| Target Affiliated Biological Pathways | Top | |||||
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| KEGG Pathway | [+] 2 KEGG Pathways | + | ||||
| 1 | Pyrimidine metabolism | |||||
| 2 | Metabolic pathways | |||||
| Panther Pathway | [+] 1 Panther Pathways | + | ||||
| 1 | De novo pyrimidine ribonucleotides biosythesis | |||||
| Pathwhiz Pathway | [+] 1 Pathwhiz Pathways | + | ||||
| 1 | Pyrimidine Metabolism | |||||
| WikiPathways | [+] 1 WikiPathways | + | ||||
| 1 | Metabolism of nucleotides | |||||
| References | Top | |||||
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| REF 1 | Molecular approaches for the treatment of hemorrhagic fever virus infections. Antiviral Res. 1993 Sep;22(1):45-75. | |||||
| REF 2 | Phase I clinical trial of continuous infusion cyclopentenyl cytosine. Cancer Chemother Pharmacol. 1995;36(6):513-23. | |||||
| REF 3 | Synergistic effects with inhibitors of de novo pyrimidine synthesis, acivicin, and N-(phosphonacetyl)-L-aspartic acid. Cancer Res. 1981 Sep;41(9 Pt 1):3419-23. | |||||
| REF 4 | Trypanosoma brucei CTP synthetase: a target for the treatment of African sleeping sickness. Proc Natl Acad Sci U S A. 2001 May 22;98(11):6412-6. | |||||
| REF 5 | How many drug targets are there Nat Rev Drug Discov. 2006 Dec;5(12):993-6. | |||||
| REF 6 | Potent activity of 5-fluoro-2'-deoxyuridine and related compounds against thymidine kinase-deficient (TK-) herpes simplex virus: targeted at thymidylate synthase. Mol Pharmacol. 1987 Aug;32(1):286-92. | |||||
| REF 7 | Comments on: cylopentenyl cytosine inhibits cytidine triphosphate synthetase in paediatric acute non-lymphocytic leukaemia: a promising target for chemotherapy. A.C. Verschuur et al. Eur J Cancer 2000, 36, 627-635. Eur J Cancer. 2001 Jan;37(2):290. | |||||
| REF 8 | Structural basis for isoform-specific inhibition of human CTPS1. Proc Natl Acad Sci U S A. 2021 Oct 5;118(40):e2107968118. | |||||
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