Target Information
| Target General Information | Top | |||||
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| Target ID |
T23292
(Former ID: TTDI02272)
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| Target Name |
N-acetylgalactosamine 6 sulfatase (GALNS)
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| Synonyms |
N-acetylgalactosamine-6-sulfate sulfatase; N-acetylgalactosamine-6-sulfatase; Galactose-6-sulfate sulfatase; GalNAc6S sulfatase; GalN6S; Chondroitinsulfatase; Chondroitinase
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| Gene Name |
GALNS
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| Target Type |
Successful target
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[1] | ||||
| Disease | [+] 1 Target-related Diseases | + | ||||
| 1 | Lysosomal disease [ICD-11: 5C56] | |||||
| Function |
Catalyzes the chemical reaction of cleaving off the 6-sulfate groups of the N-acetyl-D-galactosamine 6-sulfate units of the macromolecule chondroitin sulfate and, similarly, of the D-galactose 6-sulfate units of the macromolecule keratan sulfate.
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| BioChemical Class |
Sulfuric ester hydrolase
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| UniProt ID | ||||||
| EC Number |
EC 3.1.6.4
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| Sequence |
MAAVVAATRWWQLLLVLSAAGMGASGAPQPPNILLLLMDDMGWGDLGVYGEPSRETPNLD
RMAAEGLLFPNFYSANPLCSPSRAALLTGRLPIRNGFYTTNAHARNAYTPQEIVGGIPDS EQLLPELLKKAGYVSKIVGKWHLGHRPQFHPLKHGFDEWFGSPNCHFGPYDNKARPNIPV YRDWEMVGRYYEEFPINLKTGEANLTQIYLQEALDFIKRQARHHPFFLYWAVDATHAPVY ASKPFLGTSQRGRYGDAVREIDDSIGKILELLQDLHVADNTFVFFTSDNGAALISAPEQG GSNGPFLCGKQTTFEGGMREPALAWWPGHVTAGQVSHQLGSIMDLFTTSLALAGLTPPSD RAIDGLNLLPTLLQGRLMDRPIFYYRGDTLMAATLGQHKAHFWTWTNSWENFRQGIDFCP GQNVSGVTTHNLEDHTKLPLIFHLGRDPGERFPLSFASAEYQEALSRITSVVQQHQEALV PAQPQLNVCNWAVMNWAPPGCEKLGKCLTPPESIPKKCLWSH 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) | [+] 1 Approved Drugs | + | ||||
| 1 | Elosulfase alfa | Drug Info | Approved | Mucopolysaccharidosis | [1], [2] | |
| Clinical Trial Drug(s) | [+] 1 Clinical Trial Drugs | + | ||||
| 1 | BMN-110 | Drug Info | Phase 3 | Morquio syndrome | [3] | |
| Mode of Action | [+] 1 Modes of Action | + | ||||
| Modulator | [+] 2 Modulator drugs | + | ||||
| 1 | Elosulfase alfa | Drug Info | [1], [4] | |||
| 2 | BMN-110 | 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: 3,3-Dihydroxy l-alanine | Ligand Info | |||||
| Structure Description | The molecular basis of mucopolysaccharidosis IV A, complex with GalNAc | PDB:4FDJ | ||||
| Method | X-ray diffraction | Resolution | 2.81 Å | Mutation | No | [6] |
| PDB Sequence |
PQPPNILLLL
37 MDDMGWGDLG47 VYGEPSRETP57 NLDRMAAEGL67 LFPNFYSANP77 LSPSRAALLT 88 GRLPIRNGFY98 TTNAHARNAY108 TPQEIVGGIP118 DSEQLLPELL128 KKAGYVSKIV 138 GKWHLGHRPQ148 FHPLKHGFDE158 WFGSPNCHFG168 PYDNKARPNI178 PVYRDWEMVG 188 RYYEEFPINL198 KTGEANLTQI208 YLQEALDFIK218 RQARHHPFFL228 YWAVDATHAP 238 VYASKPFLGT248 SQRGRYGDAV258 REIDDSIGKI268 LELLQDLHVA278 DNTFVFFTSD 288 NGAALISAPE298 QGGSNGPFLC308 GKQTTFEGGM318 REPALAWWPG328 HVTAGQVSHQ 338 LGSIMDLFTT348 SLALAGLTPP358 SDRAIDGLNL368 LPTLLQGRLM378 DRPIFYYRGD 388 TLMAATLGQH398 KAHFWTWTNS408 WENFRQGIDF418 CPGQNVSGVT428 THNLEDHTKL 438 PLIFHLGRDP448 GERFPLSFAS458 AEYQEALSRI468 TSVVQQHQEA478 LVPAQPQLNV 488 CNWAVMNWAP498 PGCEKLGKCL508 TPPESIPKKC518 LW
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| Ligand Name: N-Acetyl-beta-D-galactosamine | Ligand Info | |||||
| Structure Description | The molecular basis of mucopolysaccharidosis IV A, complex with GalNAc | PDB:4FDJ | ||||
| Method | X-ray diffraction | Resolution | 2.81 Å | Mutation | No | [6] |
| PDB Sequence |
PQPPNILLLL
37 MDDMGWGDLG47 VYGEPSRETP57 NLDRMAAEGL67 LFPNFYSANP77 LSPSRAALLT 88 GRLPIRNGFY98 TTNAHARNAY108 TPQEIVGGIP118 DSEQLLPELL128 KKAGYVSKIV 138 GKWHLGHRPQ148 FHPLKHGFDE158 WFGSPNCHFG168 PYDNKARPNI178 PVYRDWEMVG 188 RYYEEFPINL198 KTGEANLTQI208 YLQEALDFIK218 RQARHHPFFL228 YWAVDATHAP 238 VYASKPFLGT248 SQRGRYGDAV258 REIDDSIGKI268 LELLQDLHVA278 DNTFVFFTSD 288 NGAALISAPE298 QGGSNGPFLC308 GKQTTFEGGM318 REPALAWWPG328 HVTAGQVSHQ 338 LGSIMDLFTT348 SLALAGLTPP358 SDRAIDGLNL368 LPTLLQGRLM378 DRPIFYYRGD 388 TLMAATLGQH398 KAHFWTWTNS408 WENFRQGIDF418 CPGQNVSGVT428 THNLEDHTKL 438 PLIFHLGRDP448 GERFPLSFAS458 AEYQEALSRI468 TSVVQQHQEA478 LVPAQPQLNV 488 CNWAVMNWAP498 PGCEKLGKCL508 TPPESIPKKC518 LW
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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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| Glycosaminoglycan degradation | hsa00531 | Affiliated Target |
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| Class: Metabolism => Glycan biosynthesis and metabolism | Pathway Hierarchy | ||
| Lysosome | hsa04142 | Affiliated Target |
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| Class: Cellular Processes => Transport and catabolism | Pathway Hierarchy | ||
| Degree | 2 | Degree centrality | 2.15E-04 | Betweenness centrality | 0.00E+00 |
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| Closeness centrality | 1.20E-01 | Radiality | 1.05E+01 | Clustering coefficient | 1.00E+00 |
| Neighborhood connectivity | 5.50E+00 | Topological coefficient | 6.88E-01 | Eccentricity | 14 |
| 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 | Chondroitin sulfate degradation (metazoa) | |||||
| KEGG Pathway | [+] 3 KEGG Pathways | + | ||||
| 1 | Glycosaminoglycan degradation | |||||
| 2 | Metabolic pathways | |||||
| 3 | Lysosome | |||||
| References | Top | |||||
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| REF 1 | 2014 FDA drug approvals. Nat Rev Drug Discov. 2015 Feb;14(2):77-81. | |||||
| 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: 7392). | |||||
| REF 3 | ClinicalTrials.gov (NCT01415427) Long-Term Efficacy and Safety Extension Study of BMN 110 in Patients With Mucopolysaccharidosis IVA (Morquio A Syndrome). U.S. National Institutes of Health. | |||||
| REF 4 | Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015 | |||||
| REF 5 | Efficacy and safety of enzyme replacement therapy with BMN 110 (elosulfase alfa) for Morquio A syndrome (mucopolysaccharidosis IVA): a phase 3 randomised placebo-controlled study. J Inherit Metab Dis. 2014 Nov;37(6):979-90. | |||||
| REF 6 | The structure of human GALNS reveals the molecular basis for mucopolysaccharidosis IV A. J Mol Biol. 2012 Nov 9;423(5):736-51. | |||||
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