Target Information
| Target General Information | Top | |||||
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| Target ID |
T31956
(Former ID: TTDR00531)
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| Target Name |
Glutamyl aminopeptidase (ENPEP)
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| Synonyms |
ENPEP; EAP; Differentiation antigen gp160; Aminopeptidase A; APA
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| Gene Name |
ENPEP
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| Target Type |
Clinical trial target
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[1] | ||||
| Disease | [+] 1 Target-related Diseases | + | ||||
| 1 | Hypertension [ICD-11: BA00-BA04] | |||||
| Function |
Appears to have a role in the catabolicpathway of the renin-angiotensin system. Probably plays a role in regulating growth and differentiation of early B-lineage cells.
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| BioChemical Class |
Peptidase
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| UniProt ID | ||||||
| EC Number |
EC 3.4.11.7
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| Sequence |
MNFAEREGSKRYCIQTKHVAILCAVVVGVGLIVGLAVGLTRSCDSSGDGGPGTAPAPSHL
PSSTASPSGPPAQDQDICPASEDESGQWKNFRLPDFVNPVHYDLHVKPLLEEDTYTGTVS ISINLSAPTRYLWLHLRETRITRLPELKRPSGDQVQVRRCFEYKKQEYVVVEAEEELTPS SGDGLYLLTMEFAGWLNGSLVGFYRTTYTENGQVKSIVATDHEPTDARKSFPCFDEPNKK ATYTISITHPKEYGALSNMPVAKEESVDDKWTRTTFEKSVPMSTYLVCFAVHQFDSVKRI SNSGKPLTIYVQPEQKHTAEYAANITKSVFDYFEEYFAMNYSLPKLDKIAIPDFGTGAME NWGLITYRETNLLYDPKESASSNQQRVATVVAHELVHQWFGNIVTMDWWEDLWLNEGFAS FFEFLGVNHAETDWQMRDQMLLEDVLPVQEDDSLMSSHPIIVTVTTPDEITSVFDGISYS KGSSILRMLEDWIKPENFQKGCQMYLEKYQFKNAKTSDFWAALEEASRLPVKEVMDTWTR QMGYPVLNVNGVKNITQKRFLLDPRANPSQPPSDLGYTWNIPVKWTEDNITSSVLFNRSE KEGITLNSSNPSGNAFLKINPDHIGFYRVNYEVATWDSIATALSLNHKTFSSADRASLID DAFALARAQLLDYKVALNLTKYLKREENFLPWQRVISAVTYIISMFEDDKELYPMIEEYF QGQVKPIADSLGWNDAGDHVTKLLRSSVLGFACKMGDREALNNASSLFEQWLNGTVSLPV NLRLLVYRYGMQNSGNEISWNYTLEQYQKTSLAQEKEKLLYGLASVKNVTLLSRYLDLLK DTNLIKTQDVFTVIRYISYNSYGKNMAWNWIQLNWDYLVNRYTLNNRNLGRIVTIAEPFN TELQLWQMESFFAKYPQAGAGEKPREQVLETVKNNIEWLKQHRNTIREWFFNLLESG Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | PDB | ||||
| HIT2.0 ID | T24GGY | |||||
| Drugs and Modes of Action | Top | |||||
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| Clinical Trial Drug(s) | [+] 1 Clinical Trial Drugs | + | ||||
| 1 | QGC-001 | Drug Info | Phase 2 | Hypertension | [2] | |
| Mode of Action | [+] 1 Modes of Action | + | ||||
| Inhibitor | [+] 4 Inhibitor drugs | + | ||||
| 1 | QGC-001 | Drug Info | [1] | |||
| 2 | EC33 | Drug Info | [3] | |||
| 3 | KELATORPHAN | Drug Info | [4] | |||
| 4 | PMID10602705C40 | Drug Info | [5] | |||
| 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: Arginine | Ligand Info | |||||
| Structure Description | Crystal structure of human aminopeptidase A complexed with arginine | PDB:4KX9 | ||||
| Method | X-ray diffraction | Resolution | 2.25 Å | Mutation | Yes | [6] |
| PDB Sequence |
DICPASEDES
85 GQWKNFRLPD95 FVNPVHYDLH105 VKPLLEEDTY115 TGTVSISINL125 SAPTRYLWLH 135 LRETRITRLP145 ELKRPSGDQV155 QVRRCFEYKK165 QEYVVVEAEE175 ELTPSSGDGL 185 YLLTMEFAGW195 LNGSLVGFYR205 TTYTENGRVK215 SIAATDHEPT225 DARKSFPCFD 235 EPNKKATYTI245 SITHPKEYGA255 LSNMPVAKEE265 SVDDKWTRTT275 FEKSVPMSTY 285 LVCFAVHQFD295 SVKRISNSGK305 PLTIYVQPEQ315 KHTAEYAANI325 TKSVFDYFEE 335 YFAMNYSLPK345 LDKIAIPDFG355 TGAMENWGLI365 TYRETNLLYD375 PKESASSNQQ 385 RVATVVAHEL395 VHQWFGNIVT405 MDWWEDLWLN415 EGFASFFEFL425 GVNHAETDWQ 435 MRDQMLLEDV445 LPVQEDDSLM455 SSHPIIVTVT465 TPDEITSVFD475 GISYSKGSSI 485 LRMLEDWIKP495 ENFQKGCQMY505 LEKYQFKNAK515 TSDFWAALEE525 ASRLPVKEVM 535 DTWTRQMGYP545 VLNVNGVKNI555 TQKRFLLDPR565 ANPSQPPSDL575 GYTWNIPVKW 585 TEDNITSSVL595 FNRSEKEGIT605 LNSGNAFLKI619 NPDHIGFYRV629 NYEVATWDSI 639 ATALSLNHKT649 FSSADRASLI659 DDAFALARAQ669 LLDYKVALNL679 TKYLKREENF 689 LPWQRVISAV699 TYIISMFEDD709 KELYPMIEEY719 FQGQVKPIAD729 SLGWNDAGDH 739 VTKLLRSSVL749 GFACKMGDRE759 ALNNASSLFE769 QWLNGTVSLP779 VNLRLLVYRY 789 GMQNSGNEIS799 WNYTLEQYQK809 TSLAQEKEKL819 LYGLASVKNV829 TLLSRYLDLL 839 KDTNLIKTQD849 VFTVIRYISY859 NSYGKNMAWN869 WIQLNWDYLV879 NRYTLNNRNL 889 GRIVTIAEPF899 NTELQLWQME909 SFFAKYPQAG919 AGEKPREQVL929 ETVKNNIEWL 939 KQHRNTIREW949 FFNLL
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| Ligand Name: Bestatin | Ligand Info | |||||
| Structure Description | Crystal structure of human aminopeptidase A complexed with bestatin | PDB:4KXB | ||||
| Method | X-ray diffraction | Resolution | 2.40 Å | Mutation | Yes | [6] |
| PDB Sequence |
DICPASEDES
85 GQWKNFRLPD95 FVNPVHYDLH105 VKPLLEEDTY115 TGTVSISINL125 SAPTRYLWLH 135 LRETRITRLP145 ELKRPSGDQV155 QVRRCFEYKK165 QEYVVVEAEE175 ELTPSSGDGL 185 YLLTMEFAGW195 LNGSLVGFYR205 TTYTENGRVK215 SIAATDHEPT225 DARKSFPCFD 235 EPNKKATYTI245 SITHPKEYGA255 LSNMPVAKEE265 SVDDKWTRTT275 FEKSVPMSTY 285 LVCFAVHQFD295 SVKRISNSGK305 PLTIYVQPEQ315 KHTAEYAANI325 TKSVFDYFEE 335 YFAMNYSLPK345 LDKIAIPDFG355 TGAMENWGLI365 TYRETNLLYD375 PKESASSNQQ 385 RVATVVAHEL395 VHQWFGNIVT405 MDWWEDLWLN415 EGFASFFEFL425 GVNHAETDWQ 435 MRDQMLLEDV445 LPVQEDDSLM455 SSHPIIVTVT465 TPDEITSVFD475 GISYSKGSSI 485 LRMLEDWIKP495 ENFQKGCQMY505 LEKYQFKNAK515 TSDFWAALEE525 ASRLPVKEVM 535 DTWTRQMGYP545 VLNVNGVKNI555 TQKRFLLDPR565 ANPSQPPSDL575 GYTWNIPVKW 585 TEDNITSSVL595 FNRSEKEGIT605 LNSGNAFLKI619 NPDHIGFYRV629 NYEVATWDSI 639 ATALSLNHKT649 FSSADRASLI659 DDAFALARAQ669 LLDYKVALNL679 TKYLKREENF 689 LPWQRVISAV699 TYIISMFEDD709 KELYPMIEEY719 FQGQVKPIAD729 SLGWNDAGDH 739 VTKLLRSSVL749 GFACKMGDRE759 ALNNASSLFE769 QWLNGTVSLP779 VNLRLLVYRY 789 GMQNSGNEIS799 WNYTLEQYQK809 TSLAQEKEKL819 LYGLASVKNV829 TLLSRYLDLL 839 KDTNLIKTQD849 VFTVIRYISY859 NSYGKNMAWN869 WIQLNWDYLV879 NRYTLNNRNL 889 GRIVTIAEPF899 NTELQLWQME909 SFFAKYPQAG919 AGEKPREQVL929 ETVKNNIEWL 939 KQHRNTIREW949 FFNLL
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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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| Protein Name | Pfam ID | Percentage of Identity (%) | E value |
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| Cofactor of initiator function (CIF) | 19.171 (37/193) | 4.00E-03 | |
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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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| Renin-angiotensin system | hsa04614 | Affiliated Target |
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| Class: Organismal Systems => Endocrine system | Pathway Hierarchy | ||
| Degree | 2 | Degree centrality | 2.15E-04 | Betweenness centrality | 1.69E-05 |
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| Closeness centrality | 1.94E-01 | Radiality | 1.33E+01 | Clustering coefficient | 0.00E+00 |
| Neighborhood connectivity | 2.90E+01 | Topological coefficient | 5.00E-01 | Eccentricity | 12 |
| Download | Click to Download the Full PPI Network of This Target | ||||
| Chemical Structure based Activity Landscape of Target | Top |
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| 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 | [+] 1 KEGG Pathways | + | ||||
| 1 | Renin-angiotensin system | |||||
| NetPath Pathway | [+] 1 NetPath Pathways | + | ||||
| 1 | IL2 Signaling Pathway | |||||
| Reactome | [+] 1 Reactome Pathways | + | ||||
| 1 | Metabolism of Angiotensinogen to Angiotensins | |||||
| WikiPathways | [+] 1 WikiPathways | + | ||||
| 1 | Metabolism of Angiotensinogen to Angiotensins | |||||
| Target-Related Models and Studies | Top | |||||
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| Target Validation | ||||||
| References | Top | |||||
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| REF 1 | Clinical pipeline report, company report or official report of Quantum Genomics. | |||||
| REF 2 | ClinicalTrials.gov (NCT02322450) Phase IIa Study of the Product QGC001 Compared With Placebo in Patients With Essential Hypertension. U.S. National Institutes of Health. | |||||
| REF 3 | Aminopeptidase A, which generates one of the main effector peptides of the brain renin-angiotensin system, angiotensin III, has a key role in central control of arterial blood pressure. Biochem Soc Trans. 2000;28(4):435-40. | |||||
| REF 4 | Retro-inverso concept applied to the complete inhibitors of enkephalin-degrading enzymes. J Med Chem. 1988 Sep;31(9):1825-31. | |||||
| REF 5 | Investigation of subsite preferences in aminopeptidase A (EC 3.4.11.7) led to the design of the first highly potent and selective inhibitors of this enzyme. J Med Chem. 1999 Dec 16;42(25):5197-211. | |||||
| REF 6 | Structural insights into central hypertension regulation by human aminopeptidase A. J Biol Chem. 2013 Aug 30;288(35):25638-25645. | |||||
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