Target Information
| Target General Information | Top | |||||
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| Target ID |
T03661
(Former ID: TTDS00092)
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| Target Name |
Adenosine deaminase (ADA)
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| Synonyms |
Adenosine aminohydrolase; ADA1
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| Gene Name |
ADA
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| Target Type |
Successful target
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[1] | ||||
| Disease | [+] 3 Target-related Diseases | + | ||||
| 1 | Adaptive immunity immunodeficiency [ICD-11: 4A01] | |||||
| 2 | Malignant haematopoietic neoplasm [ICD-11: 2B33] | |||||
| 3 | Mature B-cell leukaemia [ICD-11: 2A82] | |||||
| Function |
Plays an important role in purine metabolism and in adenosine homeostasis. Modulates signaling by extracellular adenosine, and so contributes indirectly to cellular signaling events. Acts as a positive regulator of T-cell coactivation, by binding DPP4. Its interaction with DPP4 regulates lymphocyte-epithelial cell adhesion. Enhances dendritic cell immunogenicity by affecting dendritic cell costimulatory molecule expression and cytokines and chemokines secretion. Enhances CD4+ T-cell differentiation and proliferation. Acts as a positive modulator of adenosine receptors ADORA1 and ADORA2A, by enhancing their ligand affinity via conformational change. Stimulates plasminogen activation. Plays a role in male fertility. Plays a protective role in early postimplantation embryonic development. Catalyzes the hydrolytic deamination of adenosine and 2-deoxyadenosine.
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| BioChemical Class |
Carbon-nitrogen hydrolase
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| UniProt ID | ||||||
| EC Number |
EC 3.5.4.4
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| Sequence |
MAQTPAFDKPKVELHVHLDGSIKPETILYYGRRRGIALPANTAEGLLNVIGMDKPLTLPD
FLAKFDYYMPAIAGCREAIKRIAYEFVEMKAKEGVVYVEVRYSPHLLANSKVEPIPWNQA EGDLTPDEVVALVGQGLQEGERDFGVKARSILCCMRHQPNWSPKVVELCKKYQQQTVVAI DLAGDETIPGSSLLPGHVQAYQEAVKSGIHRTVHAGEVGSAEVVKEAVDILKTERLGHGY HTLEDQALYNRLRQENMHFEICPWSSYLTGAWKPDTEHAVIRLKNDQANYSLNTDDPLIF KSTLDTDYQMTKRDMGFTEEEFKRLNINAAKSSFLPEDEKRELLDLLYKAYGMPPSASAG QNL Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | AlphaFold | ||||
| ADReCS ID | BADD_A05955 ; BADD_A06637 | |||||
| HIT2.0 ID | T20RA0 | |||||
| Drugs and Modes of Action | Top | |||||
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| Approved Drug(s) | [+] 4 Approved Drugs | + | ||||
| 1 | Cladribine | Drug Info | Approved | Hairy cell leukaemia | [2], [3] | |
| 2 | Elapegademase | Drug Info | Approved | Adenosine deaminase defciency | [4] | |
| 3 | Fludarabine | Drug Info | Approved | Haematological malignancy | [5], [6] | |
| 4 | Pentostatin | Drug Info | Approved | Hairy cell leukaemia | [6], [7] | |
| Clinical Trial Drug(s) | [+] 3 Clinical Trial Drugs | + | ||||
| 1 | GSK2696273 | Drug Info | Preregistration | Chronic pain | [8] | |
| 2 | OTL-101 | Drug Info | Phase 3 | Severe combined immunodeficiency | [9] | |
| 3 | Ex vivo adenosine deaminase-transduced hematopoietic stem cell therapy | Drug Info | Phase 1/2 | Immunodeficiency | [10] | |
| Mode of Action | [+] 3 Modes of Action | + | ||||
| Inhibitor | [+] 25 Inhibitor drugs | + | ||||
| 1 | Cladribine | Drug Info | [1], [11] | |||
| 2 | Fludarabine | Drug Info | [12] | |||
| 3 | Pentostatin | Drug Info | [12], [13] | |||
| 4 | (2S,3R)-3-(6-amino-9H-purin-9-yl)nonan-2-ol | Drug Info | [16] | |||
| 5 | 1-Deaza-Adenosine | Drug Info | [17] | |||
| 6 | 3-(6-Amino-purin-9-yl)-4-butoxy-butan-2-ol | Drug Info | [18] | |||
| 7 | 3-(6-Amino-purin-9-yl)-4-p-tolyl-butan-2-ol | Drug Info | [18] | |||
| 8 | 3-(6-Amino-purin-9-yl)-4-phenethyloxy-butan-2-ol | Drug Info | [18] | |||
| 9 | 3-(6-Amino-purin-9-yl)-5-m-tolyl-pentan-2-ol | Drug Info | [18] | |||
| 10 | 3-(6-Amino-purin-9-yl)-6-o-tolyl-hexan-2-ol | Drug Info | [18] | |||
| 11 | 3-(6-Amino-purin-9-yl)-6-phenyl-hexan-2-ol | Drug Info | [18] | |||
| 12 | 3-(6-Amino-purin-9-yl)-7-phenyl-heptan-2-ol | Drug Info | [18] | |||
| 13 | 3-(6-Amino-purin-9-yl)-8-phenyl-octan-2-ol | Drug Info | [18] | |||
| 14 | 3-(6-Amino-purin-9-yl)-non-5-en-2-ol | Drug Info | [18] | |||
| 15 | 3-(6-Amino-purin-9-yl)-non-5-yn-2-ol | Drug Info | [18] | |||
| 16 | 6-Hydroxy-1,6-Dihydro Purine Nucleoside | Drug Info | [17] | |||
| 17 | 6-Hydroxy-7,8-Dihydro Purine Nucleoside | Drug Info | [17] | |||
| 18 | EHNA | Drug Info | [19] | |||
| 19 | FR117016 | Drug Info | [16] | |||
| 20 | FR221647 | Drug Info | [16] | |||
| 21 | FR230513 | Drug Info | [16] | |||
| 22 | FR233623 | Drug Info | [16] | |||
| 23 | FR236913 | Drug Info | [16] | |||
| 24 | FR239087 | Drug Info | [16] | |||
| 25 | Purine Riboside | Drug Info | [17] | |||
| Modulator | [+] 3 Modulator drugs | + | ||||
| 1 | Elapegademase | Drug Info | [4] | |||
| 2 | GSK2696273 | Drug Info | [14] | |||
| 3 | Ex vivo adenosine deaminase-transduced hematopoietic stem cell therapy | Drug Info | [14] | |||
| Replacement | [+] 1 Replacement drugs | + | ||||
| 1 | OTL-101 | Drug Info | [15] | |||
| 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: Deoxyadenosine | Ligand Info | |||||
| Structure Description | The crystal structure of human adenosine deaminase | PDB:3IAR | ||||
| Method | X-ray diffraction | Resolution | 1.52 Å | Mutation | No | [20] |
| PDB Sequence |
PAFDKPKVEL
14 HVHLDGSIKP24 ETILYYGRRR34 GIALPANTAE44 GLLNVIGMDK54 PLTLPDFLAK 64 FDYYMPAIAG74 CREAIKRIAY84 EFVEMKAKEG94 VVYVEVRYSP104 HLLANSKVEP 114 IPWNQAEGDL124 TPDEVVALVG134 QGLQEGERDF144 GVKARSILCC154 MRHQPNWSPK 164 VVELCKKYQQ174 QTVVAIDLAG184 DETIPGSSLL194 PGHVQAYQEA204 VKSGIHRTVH 214 AGEVGSAEVV224 KEAVDILKTE234 RLGHGYHTLE244 DQALYNRLRQ254 ENMHFEICPW 264 SSYLTGAWKP274 DTEHAVIRLK284 NDQANYSLNT294 DDPLIFKSTL304 DTDYQMTKRD 314 MGFTEEEFKR324 LNINAAKSSF334 LPEDEKRELL344 DLLYKAYGMP354 PSASAGQNLA 364
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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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| Purine metabolism | hsa00230 | Affiliated Target |
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| Class: Metabolism => Nucleotide metabolism | Pathway Hierarchy | ||
| Degree | 5 | Degree centrality | 5.37E-04 | Betweenness centrality | 1.13E-03 |
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| Closeness centrality | 1.85E-01 | Radiality | 1.31E+01 | Clustering coefficient | 3.00E-01 |
| Neighborhood connectivity | 1.10E+01 | Topological coefficient | 2.40E-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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| 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 Poor or Non Binders | Top | |||||
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| Target Poor or Non Binders | ||||||
| Target Regulators | Top | |||||
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| Target-regulating microRNAs | ||||||
| Target-regulating Transcription Factors | ||||||
| Target Affiliated Biological Pathways | Top | |||||
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| BioCyc | [+] 6 BioCyc Pathways | + | ||||
| 1 | Purine nucleotides degradation | |||||
| 2 | Purine deoxyribonucleosides degradation | |||||
| 3 | Purine ribonucleosides degradation to ribose-1-phosphate | |||||
| 4 | Adenosine nucleotides degradation | |||||
| 5 | Superpathway of purine nucleotide salvage | |||||
| 6 | Adenine and adenosine salvage III | |||||
| KEGG Pathway | [+] 3 KEGG Pathways | + | ||||
| 1 | Purine metabolism | |||||
| 2 | Metabolic pathways | |||||
| 3 | Primary immunodeficiency | |||||
| NetPath Pathway | [+] 2 NetPath Pathways | + | ||||
| 1 | TCR Signaling Pathway | |||||
| 2 | IL2 Signaling Pathway | |||||
| Panther Pathway | [+] 1 Panther Pathways | + | ||||
| 1 | Adenine and hypoxanthine salvage pathway | |||||
| Pathwhiz Pathway | [+] 1 Pathwhiz Pathways | + | ||||
| 1 | Purine Metabolism | |||||
| PID Pathway | [+] 4 PID Pathways | + | ||||
| 1 | p73 transcription factor network | |||||
| 2 | C-MYB transcription factor network | |||||
| 3 | Validated transcriptional targets of deltaNp63 isoforms | |||||
| 4 | Validated transcriptional targets of TAp63 isoforms | |||||
| Reactome | [+] 1 Reactome Pathways | + | ||||
| 1 | Purine salvage | |||||
| WikiPathways | [+] 1 WikiPathways | + | ||||
| 1 | Metabolism of nucleotides | |||||
| Target-Related Models and Studies | Top | |||||
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| Target Validation | ||||||
| References | Top | |||||
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| REF 1 | Cladribine: from the bench to the bedside--focus on hairy cell leukemia. Expert Rev Anticancer Ther. 2004 Oct;4(5):745-57. | |||||
| 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: 4799). | |||||
| REF 3 | Multiple sclerosis: current and future treatment options. Endocr Metab Immune Disord Drug Targets. 2007 Dec;7(4):292-9. | |||||
| REF 4 | 2018 FDA drug approvals.Nat Rev Drug Discov. 2019 Feb;18(2):85-89. | |||||
| REF 5 | 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: 4802). | |||||
| REF 6 | Natural products as sources of new drugs over the last 25 years. J Nat Prod. 2007 Mar;70(3):461-77. | |||||
| REF 7 | 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: 4805). | |||||
| REF 8 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800033647) | |||||
| REF 9 | ClinicalTrials.gov (NCT04140539) A Clinical Study to Enable Process Validation of Commercial Grade OTL-101. U.S. National Institutes of Health. | |||||
| REF 10 | Clinical pipeline report, company report or official report of GlaxoSmithKline. | |||||
| REF 11 | Cladribine. Ortho Biotech Inc. Curr Opin Investig Drugs. 2001 Dec;2(12):1751-6. | |||||
| REF 12 | Purine nucleoside analogs in indolent non-Hodgkin's lymphoma. Oncology (Williston Park). 2000 Jun;14(6 Suppl 2):13-5. | |||||
| REF 13 | Acquisition of resistance to anticancer agents by overproduction of target enzymes. Nippon Rinsho. 1997 May;55(5):1030-7. | |||||
| REF 14 | Clinical pipeline report, company report or official report of GlaxoSmithKline. | |||||
| REF 15 | Clinical pipeline report, company report or official report of Orchard Therapeutics. | |||||
| REF 16 | The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42. | |||||
| REF 17 | How many drug targets are there Nat Rev Drug Discov. 2006 Dec;5(12):993-6. | |||||
| REF 18 | Adenosine deaminase inhibitors: synthesis and biological evaluation of unsaturated, aromatic, and oxo derivatives of (+)-erythro-9-(2'S-hydroxy-3'R... J Med Chem. 2000 Nov 30;43(24):4694-700. | |||||
| REF 19 | Tight-binding inhibitors--IV. Inhibition of adenosine deaminases by various inhibitors. Biochem Pharmacol. 1977 Mar 1;26(5):359-67. | |||||
| REF 20 | The crystal structure of human adenosine deaminase | |||||
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