Target Information
| Target General Information | Top | |||||
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| Target ID |
T25163
(Former ID: TTDS00533)
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| Target Name |
Carbamoyl-phosphate synthetase I (CPS1)
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| Synonyms |
Carbamoyl-phosphate synthase [ammonia], mitochondrial; CPSase I; CPS1
Click to Show/Hide
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| Gene Name |
CPS1
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| Target Type |
Successful target
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[1] | ||||
| Disease | [+] 2 Target-related Diseases | + | ||||
| 1 | Metabolism inborn error [ICD-11: 5C50] | |||||
| 2 | Varicose veins [ICD-11: BD74-BD75] | |||||
| Function |
Involved in the urea cycle of ureotelic animals where the enzyme plays an important role in removing excess ammonia from the cell.
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| BioChemical Class |
Carbon-nitrogen ligase
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| UniProt ID | ||||||
| EC Number |
EC 6.3.4.16
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| Sequence |
MTRILTAFKVVRTLKTGFGFTNVTAHQKWKFSRPGIRLLSVKAQTAHIVLEDGTKMKGYS
FGHPSSVAGEVVFNTGLGGYPEAITDPAYKGQILTMANPIIGNGGAPDTTALDELGLSKY LESNGIKVSGLLVLDYSKDYNHWLATKSLGQWLQEEKVPAIYGVDTRMLTKIIRDKGTML GKIEFEGQPVDFVDPNKQNLIAEVSTKDVKVYGKGNPTKVVAVDCGIKNNVIRLLVKRGA EVHLVPWNHDFTKMEYDGILIAGGPGNPALAEPLIQNVRKILESDRKEPLFGISTGNLIT GLAAGAKTYKMSMANRGQNQPVLNITNKQAFITAQNHGYALDNTLPAGWKPLFVNVNDQT NEGIMHESKPFFAVQFHPEVTPGPIDTEYLFDSFFSLIKKGKATTITSVLPKPALVASRV EVSKVLILGSGGLSIGQAGEFDYSGSQAVKAMKEENVKTVLMNPNIASVQTNEVGLKQAD TVYFLPITPQFVTEVIKAEQPDGLILGMGGQTALNCGVELFKRGVLKEYGVKVLGTSVES IMATEDRQLFSDKLNEINEKIAPSFAVESIEDALKAADTIGYPVMIRSAYALGGLGSGIC PNRETLMDLSTKAFAMTNQILVEKSVTGWKEIEYEVVRDADDNCVTVCNMENVDAMGVHT GDSVVVAPAQTLSNAEFQMLRRTSINVVRHLGIVGECNIQFALHPTSMEYCIIEVNARLS RSSALASKATGYPLAFIAAKIALGIPLPEIKNVVSGKTSACFEPSLDYMVTKIPRWDLDR FHGTSSRIGSSMKSVGEVMAIGRTFEESFQKALRMCHPSIEGFTPRLPMNKEWPSNLDLR KELSEPSSTRIYAIAKAIDDNMSLDEIEKLTYIDKWFLYKMRDILNMEKTLKGLNSESMT EETLKRAKEIGFSDKQISKCLGLTEAQTRELRLKKNIHPWVKQIDTLAAEYPSVTNYLYV TYNGQEHDVNFDDHGMMVLGCGPYHIGSSVEFDWCAVSSIRTLRQLGKKTVVVNCNPETV STDFDECDKLYFEELSLERILDIYHQEACGGCIISVGGQIPNNLAVPLYKNGVKIMGTSP LQIDRAEDRSIFSAVLDELKVAQAPWKAVNTLNEALEFAKSVDYPCLLRPSYVLSGSAMN VVFSEDEMKKFLEEATRVSQEHPVVLTKFVEGAREVEMDAVGKDGRVISHAISEHVEDAG VHSGDATLMLPTQTISQGAIEKVKDATRKIAKAFAISGPFNVQFLVKGNDVLVIECNLRA SRSFPFVSKTLGVDFIDVATKVMIGENVDEKHLPTLDHPIIPADYVAIKAPMFSWPRLRD ADPILRCEMASTGEVACFGEGIHTAFLKAMLSTGFKIPQKGILIGIQQSFRPRFLGVAEQ LHNEGFKLFATEATSDWLNANNVPATPVAWPSQEGQNPSLSSIRKLIRDGSIDLVINLPN NNTKFVHDNYVIRRTAVDSGIPLLTNFQVTKLFAEAVQKSRKVDSKSLFHYRQYSAGKAA 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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| Approved Drug(s) | [+] 2 Approved Drugs | + | ||||
| 1 | Carglumic acid | Drug Info | Approved | Acute hyperammonaemia | [1], [2] | |
| 2 | Polidocanol - BioForm Medical/Chemische Fabrik Kreussler & Co | Drug Info | Approved | Varicose veins | [3] | |
| Mode of Action | [+] 2 Modes of Action | + | ||||
| Activator | [+] 1 Activator drugs | + | ||||
| 1 | Carglumic acid | Drug Info | [1] | |||
| Modulator | [+] 1 Modulator drugs | + | ||||
| 1 | Polidocanol - BioForm Medical/Chemische Fabrik Kreussler & Co | Drug Info | [1] | |||
| 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: adenosine diphosphate | Ligand Info | |||||
| Structure Description | Crystal Structure of Human Carbamoyl phosphate synthetase I (CPS1), ligand-bound form | PDB:5DOU | ||||
| Method | X-ray diffraction | Resolution | 2.60 Å | Mutation | No | [4] |
| PDB Sequence |
AQTAHIVLED
52 GTKMKGYSFG62 HPSSVAGEVV72 FNTGLGGYPE82 AITDPAYKGQ92 ILTMANPIIG 102 NGGAPDTTAL112 DELGLSKYLE122 SNGIKVSGLL132 VLDYSKDYNH142 WLATKSLGQW 152 LQEEKVPAIY162 GVDTRMLTKI172 IRDKGTMLGK182 IEFEGQPVDF192 VDPNKQNLIA 202 EVSTKDVKVY212 GKGNPTKVVA222 VDCGIKNNVI232 RLLVKRGAEV242 HLVPWNHDFT 252 KMEYDGILIA262 GGPGNPALAE272 PLIQNVRKIL282 ESDRKEPLFG292 ISTGNLITGL 302 AAGAKTYKMS312 MANRGQNQPV322 LNITNKQAFI332 TAQNHGYALD342 NTLPAGWKPL 352 FVNVNDQTNE362 GIMHESKPFF372 AVQFHPEVTP382 GPIDTEYLFD392 SFFSLIKKGK 402 ATTITSVLPK412 PALVASRVEV422 SKVLILGSGG432 LSIGQAGEFD442 YSGSQAVKAM 452 KEENVKTVLM462 NPNIASVQTN472 EVGLKQADTV482 YFLPITPQFV492 TEVIKAEQPD 502 GLILGMGGQT512 ALNCGVELFK522 RGVLKEYGVK532 VLGTSVESIM542 ATEDRQLFSD 552 KLNEINEKIA562 PSFAVESIED572 ALKAADTIGY582 PVMIRSAYAL592 GGLGSGICPN 602 RETLMDLSTK612 AFAMTNQILV622 EKSVTGWKEI632 EYEVVRDADD642 NCVTVCNMEN 652 VDAMGVHTGD662 SVVVAPAQTL672 SNAEFQMLRR682 TSINVVRHLG692 IVGECNIQFA 702 LHPTSMEYCI712 IEVNARLSRS722 SALASKATGY732 PLAFIAAKIA742 LGIPLPEIKN 752 VVSGKTSACF762 EPSLDYMVTK772 IPRWDLDRFH782 GTSSRIGSSM792 KSVGEVMAIG 802 RTFEESFQKA812 LRMCHPSIEG822 FTPRLPMNKE832 WPSNLDLRKE842 LSEPSSTRIY 852 AIAKAIDDNM862 SLDEIEKLTY872 IDKWFLYKMR882 DILNMEKTLK892 GLNSESMTEE 902 TLKRAKEIGF912 SDKQISKCLG922 LTEAQTRELR932 LKKNIHPWVK942 QIDTLAAEYP 952 SVTNYLYVTY962 NGQEHDVNFD972 DHGMMVLGCG982 PYHIGSSVEF992 DWCAVSSIRT 1002 LRQLGKKTVV1012 VNCNPETVST1022 DFDECDKLYF1032 EELSLERILD1042 IYHQEACGGC 1052 IISVGGQIPN1062 NLAVPLYKNG1072 VKIMGTSPLQ1082 IDRAEDRSIF1092 SAVLDELKVA 1102 QAPWKAVNTL1112 NEALEFAKSV1122 DYPCLLRMNV1141 VFSEDPVVLT1167 KFVEGAREVE 1177 MDAVGKDGRV1187 ISHAISEHVE1197 DAGVHSGDAT1207 LMLPTQTISQ1217 GAIEKVKDAT 1227 RKIAKAFAIS1237 GPFNVQFLVK1247 GNDVLVIECN1257 LRASRSFPFV1267 SKTLGVDFID 1277 VATKVMIGEN1287 VDEKHLPTLD1297 HPIIPADYVA1307 IKAPMFSWPR1317 LRDADPILRC 1327 EMASTGEVAC1337 FGEGIHTAFL1347 KAMLSTGFKI1357 PQKGILIGIQ1367 QSFRPRFLGV 1377 AEQLHNEGFK1387 LFATEATSDW1397 LNANNVPATP1407 VAWPSQEGQN1417 PSLSSIRKLI 1427 RDGSIDLVIN1437 LPNNNTKFVH1447 DNYVIRRTAV1457 DSGIPLLTNF1467 QVTKLFAEAV 1477 QKDSKSLFHY1491 RQ
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ARG547
3.250
MET585
3.551
ARG587
2.475
ALA591
3.450
LEU592
3.251
GLY593
3.264
GLY594
2.601
LEU595
4.264
ILE599
4.740
GLU623
2.634
LYS624
3.024
SER625
3.588
VAL626
2.861
THR627
3.473
GLU631
2.543
ALA655
4.699
MET656
3.557
GLY657
3.179
VAL658
3.189
HIS659
2.471
THR660
3.688
GLN700
2.719
ILE713
3.640
GLU714
2.754
ASN716
4.137
SER790
3.511
ALA1104
3.746
LEU1127
3.305
ARG1129
3.669
MET1139
3.528
THR1167
4.155
LYS1168
2.858
PHE1169
3.455
VAL1170
2.875
GLU1175
2.479
ALA1199
3.690
GLY1200
3.129
VAL1201
2.845
HIS1202
3.018
SER1203
3.207
GLN1243
3.059
LEU1245
3.491
ILE1254
3.538
GLU1255
2.934
CYS1327
3.840
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| Ligand Name: Glutarate | Ligand Info | |||||
| Structure Description | Crystal structure of zebrafish Sirtuin 5 in complex with glutarylated CPS1-peptide | PDB:4UTR | ||||
| Method | X-ray diffraction | Resolution | 2.90 Å | Mutation | Yes | [5] |
| PDB Sequence |
GVLKEYGV
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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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| Arginine biosynthesis | hsa00220 | Affiliated Target |
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| Class: Metabolism => Amino acid metabolism | Pathway Hierarchy | ||
| Alanine, aspartate and glutamate metabolism | hsa00250 | Affiliated Target |
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| Class: Metabolism => Amino acid metabolism | Pathway Hierarchy | ||
| Nitrogen metabolism | hsa00910 | Affiliated Target |
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| Class: Metabolism => Energy metabolism | Pathway Hierarchy | ||
| Degree | 4 | Degree centrality | 4.30E-04 | Betweenness centrality | 1.34E-05 |
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| Closeness centrality | 1.75E-01 | Radiality | 1.28E+01 | Clustering coefficient | 3.33E-01 |
| Neighborhood connectivity | 1.05E+01 | Topological coefficient | 3.39E-01 | Eccentricity | 13 |
| Download | Click to Download the Full PPI Network of This Target | ||||
| Target Affiliated Biological Pathways | Top | |||||
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| BioCyc | [+] 1 BioCyc Pathways | + | ||||
| 1 | Urea cycle | |||||
| KEGG Pathway | [+] 6 KEGG Pathways | + | ||||
| 1 | Alanine, aspartate and glutamate metabolism | |||||
| 2 | Arginine and proline metabolism | |||||
| 3 | Nitrogen metabolism | |||||
| 4 | Metabolic pathways | |||||
| 5 | Carbon metabolism | |||||
| 6 | Biosynthesis of amino acids | |||||
| Panther Pathway | [+] 2 Panther Pathways | + | ||||
| 1 | Arginine biosynthesis | |||||
| 2 | De novo pyrimidine ribonucleotides biosythesis | |||||
| Pathwhiz Pathway | [+] 4 Pathwhiz Pathways | + | ||||
| 1 | Glutamate Metabolism | |||||
| 2 | Ammonia Recycling | |||||
| 3 | Arginine and Proline Metabolism | |||||
| 4 | Urea Cycle | |||||
| WikiPathways | [+] 2 WikiPathways | + | ||||
| 1 | Urea cycle and metabolism of amino groups | |||||
| 2 | Metabolism of amino acids and derivatives | |||||
| References | Top | |||||
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| REF 1 | Mullard A: 2010 FDA drug approvals. Nat Rev Drug Discov. 2011 Feb;10(2):82-5. | |||||
| REF 2 | URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 7458). | |||||
| REF 3 | Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015 | |||||
| REF 4 | Structure of human carbamoyl phosphate synthetase: deciphering the on/off switch of human ureagenesis. Sci Rep. 2015 Nov 23;5:16950. | |||||
| REF 5 | Chemical probing of the human sirtuin 5 active site reveals its substrate acyl specificity and peptide-based inhibitors. Angew Chem Int Ed Engl. 2014 Sep 26;53(40):10728-32. | |||||
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