Target Information
| Target General Information | Top | |||||
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| Target ID |
T24548
(Former ID: TTDR00171)
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| Target Name |
Aspartate carbamoyltransferase (CAD)
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| Synonyms |
CAD
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| Gene Name |
CAD
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| Target Type |
Literature-reported target
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[1] | ||||
| Function |
This protein is a "fusion" protein encoding four enzymatic activities of the pyrimidine pathway (GATase, CPSase, ATCase and DHOase).
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| BioChemical Class |
Carbon-nitrogen ligase
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| UniProt ID | ||||||
| Sequence |
MAALVLEDGSVLRGQPFGAAVSTAGEVVFQTGMVGYPEALTDPSYKAQILVLTYPLIGNY
GIPPDEMDEFGLCKWFESSGIHVAALVVGECCPTPSHWSATRTLHEWLQQHGIPGLQGVD TRELTKKLREQGSLLGKLVQNGTEPSSLPFLDPNARPLVPEVSIKTPRVFNTGGAPRILA LDCGLKYNQIRCLCQRGAEVTVVPWDHALDSQEYEGLFLSNGPGDPASYPSVVSTLSRVL SEPNPRPVFGICLGHQLLALAIGAKTYKMRYGNRGHNQPCLLVGSGRCFLTSQNHGFAVE TDSLPADWAPLFTNANDGSNEGIVHNSLPFFSVQFHPEHQAGPSDMELLFDIFLETVKEA TAGNPGGQTVRERLTERLCPPGIPTPGSGLPPPRKVLILGSGGLSIGQAGEFDYSGSQAI KALKEENIQTLLINPNIATVQTSQGLADKVYFLPITPHYVTQVIRNERPDGVLLTFGGQT ALNCGVELTKAGVLARYGVRVLGTPVETIELTEDRRAFAARMAEIGEHVAPSEAANSLEQ AQAAAERLGYPVLVRAAFALGGLGSGFASNREELSALVAPAFAHTSQVLVDKSLKGWKEI EYEVVRDAYGNCVTVCNMENLDPLGIHTGESIVVAPSQTLNDREYQLLRQTAIKVTQHLG IVGECNVQYALNPESEQYYIIEVNARLSRSSALASKATGYPLAYVAAKLALGIPLPELRN SVTGGTAAFEPSVDYCVVKIPRWDLSKFLRVSTKIGSCMKSVGEVMGIGRSFEEAFQKAL RMVDENCVGFDHTVKPVSDMELETPTDKRIFVVAAALWAGYSVDRLYELTRIDRWFLHRM KRIIAHAQLLEQHRGQPLPPDLLQQAKCLGFSDKQIALAVLSTELAVRKLRQELGICPAV KQIDTVAAEWPAQTNYLYLTYWGTTHDLTFRTPHVLVLGSGVYRIGSSVEFDWCAVGCIQ QLRKMGYKTIMVNYNPETVSTDYDMCDRLYFDEISFEVVMDIYELENPEGVILSMGGQLP NNMAMALHRQQCRVLGTSPEAIDSAENRFKFSRLLDTIGISQPQWRELSDLESARQFCQT VGYPCVVRPSYVLSGAAMNVAYTDGDLERFLSSAAAVSKEHPVVISKFIQEAKEIDVDAV ASDGVVAAIAISEHVENAGVHSGDATLVTPPQDITAKTLERIKAIVHAVGQELQVTGPFN LQLIAKDDQLKVIECNVRVSRSFPFVSKTLGVDLVALATRVIMGEEVEPVGLMTGSGVVG VKVPQFSFSRLAGADVVLGVEMTSTGEVAGFGESRCEAYLKAMLSTGFKIPKKNILLTIG SYKNKSELLPTVRLLESLGYSLYASLGTADFYTEHGVKVTAVDWHFEEAVDGECPPQRSI LEQLAEKNFELVINLSMRGAGGRRLSSFVTKGYRTRRLAADFSVPLIIDIKCTKLFVEAL GQIGPAPPLKVHVDCMTSQKLVRLPGLIDVHVHLREPGGTHKEDFASGTAAALAGGITMV CAMPNTRPPIIDAPALALAQKLAEAGARCDFALFLGASSENAGTLGTVAGSAAGLKLYLN ETFSELRLDSVVQWMEHFETWPSHLPIVAHAEQQTVAAVLMVAQLTQRSVHICHVARKEE ILLIKAAKARGLPVTCEVAPHHLFLSHDDLERLGPGKGEVRPELGSRQDVEALWENMAVI DCFASDHAPHTLEEKCGSRPPPGFPGLETMLPLLLTAVSEGRLSLDDLLQRLHHNPRRIF HLPPQEDTYVEVDLEHEWTIPSHMPFSKAHWTPFEGQKVKGTVRRVVLRGEVAYIDGQVL VPPGYGQDVRKWPQGAVPQLPPSAPATSEMTTTPERPRRGIPGLPDGRFHLPPRIHRASD PGLPAEEPKEKSSRKVAEPELMGTPDGTCYPPPPVPRQASPQNLGTPGLLHPQTSPLLHS LVGQHILSVQQFTKDQMSHLFNVAHTLRMMVQKERSLDILKGKVMASMFYEVSTRTSSSF AAAMARLGGAVLSFSEATSSVQKGESLADSVQTMSCYADVVVLRHPQPGAVELAAKHCRR PVINAGDGVGEHPTQALLDIFTIREELGTVNGMTITMVGDLKHGRTVHSLACLLTQYRVS LRYVAPPSLRMPPTVRAFVASRGTKQEEFESIEEALPDTDVLYMTRIQKERFGSTQEYEA CFGQFILTPHIMTRAKKKMVVMHPMPRVNEISVEVDSDPRAAYFRQAENGMYIRMALLAT VLGRF Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | AlphaFold | ||||
| 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: Lysine Nz-Carboxylic Acid | Ligand Info | |||||
| Structure Description | Human dihydroorotase mutant F1563T co-crystallized with carbamoyl aspartate at pH 7.5 | PDB:6HFQ | ||||
| Method | X-ray diffraction | Resolution | 1.15 Å | Mutation | Yes | [2] |
| PDB Sequence |
KLVRLPGLID
1469 VHVHLREPGG1479 THKEDFASGT1489 AAALAGGITM1499 VCAMPNTRPP1509 IIDGPALALA 1519 QKLAEAGARC1529 DFALFLGASS1539 ENAGTLGTVA1549 GSAAGLLYLN1560 ETTSELRLDS 1570 VVQWMEHFET1580 WPSHLPIVAH1590 AEQQTVAAVL1600 MVAQLTQRSV1610 HICHVARKEE 1620 ILLIKAAKAR1630 GLPVTCEVAP1640 HHLFLSHDDL1650 ERLGPGKGEV1660 RPELGSRQDV 1670 EALWENMAVI1680 DCFASDHAPH1690 TLEEKCGSRP1700 PPGFPGLETM1710 LPLLLTAVSE 1720 GRLSLDDLLQ1730 RLHHNPRRIF1740 HLPPQEDTYV1750 EVDLEHEWTI1760 PSHMPFSKAH 1770 WTPFEGQKVK1780 GTVRRVVLRG1790 EVAYIDGQVL1800 VPPGYGQDVR1810 KWPQGAVPQL 1820 P
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HIS1471
2.598
HIS1473
2.579
MET1503
2.674
PRO1504
2.451
ASN1505
4.944
PHE1534
3.225
LEU1535
2.006
GLY1536
2.717
ALA1537
2.104
GLY1554
3.910
LEU1555
1.332
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| Click to View More Binding Site Information of This Target and Ligand Pair | ||||||
| Ligand Name: N-Carbamoyl-L-Aspartate | Ligand Info | |||||
| Structure Description | Crystal structure of the dihydroorotase domain of human CAD bound to substrate at pH 5.5 | PDB:4C6E | ||||
| Method | X-ray diffraction | Resolution | 1.26 Å | Mutation | No | [3] |
| PDB Sequence |
KLVRLPGLID
1469 VHVHLREPGG1479 THKEDFASGT1489 AAALAGGITM1499 VCAMPNTRPP1509 IIDAPALALA 1519 QKLAEAGARC1529 DFALFLGASS1539 ENAGTLGTVA1549 GSAAGLLYLN1560 ETFSELRLDS 1570 VVQWMEHFET1580 WPSHLPIVAH1590 AEQQTVAAVL1600 MVAQLTQRSV1610 HICHVARKEE 1620 ILLIKAAKAR1630 GLPVTCEVAP1640 HHLFLSHDDL1650 ERLGPGKGEV1660 RPELGSRQDV 1670 EALWENMAVI1680 DCFASDHAPH1690 TLEEKCGSRP1700 PPGFPGLETM1710 LPLLLTAVSE 1720 GRLSLDDLLQ1730 RLHHNPRRIF1740 HLPPQEDTYV1750 EVDLEHEWTI1760 PSHMPFSKAH 1770 WTPFEGQKVK1780 GTVRRVVLRG1790 EVAYIDGQVL1800 VPPGYGQDVR1810 KWPQGAVPQL 1820 PPS
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| Click to View More Binding Site Information of This Target and Ligand Pair | ||||||
| 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 | ||
| Alanine, aspartate and glutamate metabolism | hsa00250 | Affiliated Target |
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| Class: Metabolism => Amino acid metabolism | Pathway Hierarchy | ||
| Degree | 10 | Degree centrality | 1.07E-03 | Betweenness centrality | 7.06E-04 |
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| Closeness centrality | 1.79E-01 | Radiality | 1.30E+01 | Clustering coefficient | 8.89E-02 |
| Neighborhood connectivity | 8.10E+00 | Topological coefficient | 1.35E-01 | Eccentricity | 13 |
| Download | Click to Download the Full PPI Network of This Target | ||||
| Chemical Structure based Activity Landscape of Target | Top |
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| Target Affiliated Biological Pathways | Top | |||||
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| BioCyc | [+] 3 BioCyc Pathways | + | ||||
| 1 | Superpathway of pyrimidine deoxyribonucleotides de novo biosynthesis | |||||
| 2 | Superpathway of pyrimidine ribonucleotides de novo biosynthesis | |||||
| 3 | UMP biosynthesis | |||||
| KEGG Pathway | [+] 3 KEGG Pathways | + | ||||
| 1 | Pyrimidine metabolism | |||||
| 2 | Alanine, aspartate and glutamate metabolism | |||||
| 3 | Metabolic pathways | |||||
| NetPath Pathway | [+] 2 NetPath Pathways | + | ||||
| 1 | EGFR1 Signaling Pathway | |||||
| 2 | TGF_beta_Receptor Signaling Pathway | |||||
| Panther Pathway | [+] 2 Panther Pathways | + | ||||
| 1 | Arginine biosynthesis | |||||
| 2 | De novo pyrimidine ribonucleotides biosythesis | |||||
| Pathwhiz Pathway | [+] 3 Pathwhiz Pathways | + | ||||
| 1 | Aspartate Metabolism | |||||
| 2 | Glutamate Metabolism | |||||
| 3 | Pyrimidine Metabolism | |||||
| PID Pathway | [+] 1 PID Pathways | + | ||||
| 1 | Validated targets of C-MYC transcriptional activation | |||||
| Reactome | [+] 1 Reactome Pathways | + | ||||
| 1 | Pyrimidine biosynthesis | |||||
| WikiPathways | [+] 2 WikiPathways | + | ||||
| 1 | Endothelin Pathways | |||||
| 2 | Metabolism of nucleotides | |||||
| References | Top | |||||
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| REF 1 | How many drug targets are there Nat Rev Drug Discov. 2006 Dec;5(12):993-6. | |||||
| REF 2 | Characterization of the catalytic flexible loop in the dihydroorotase domain of the human multi-enzymatic protein CAD. J Biol Chem. 2018 Dec 7;293(49):18903-18913. | |||||
| REF 3 | Structure, functional characterization, and evolution of the dihydroorotase domain of human CAD. Structure. 2014 Feb 4;22(2):185-98. | |||||
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