Target Information
| Target General Information | Top | |||||
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| Target ID |
T98157
(Former ID: TTDI02021)
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| Target Name |
Cerebroside-sulfatase (ARSA)
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| Synonyms |
Cerebrosidesulfatase; Arylsulfatase A component C; ASA; ARSA
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| Gene Name |
ARSA
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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 |
Hydrolyzes cerebroside sulfate.
Click to Show/Hide
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| BioChemical Class |
Sulfuric ester hydrolase
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| UniProt ID | ||||||
| EC Number |
EC 3.1.6.8
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| Sequence |
MGAPRSLLLALAAGLAVARPPNIVLIFADDLGYGDLGCYGHPSSTTPNLDQLAAGGLRFT
DFYVPVSLCTPSRAALLTGRLPVRMGMYPGVLVPSSRGGLPLEEVTVAEVLAARGYLTGM AGKWHLGVGPEGAFLPPHQGFHRFLGIPYSHDQGPCQNLTCFPPATPCDGGCDQGLVPIP LLANLSVEAQPPWLPGLEARYMAFAHDLMADAQRQDRPFFLYYASHHTHYPQFSGQSFAE RSGRGPFGDSLMELDAAVGTLMTAIGDLGLLEETLVIFTADNGPETMRMSRGGCSGLLRC GKGTTYEGGVREPALAFWPGHIAPGVTHELASSLDLLPTLAALAGAPLPNVTLDGFDLSP LLLGTGKSPRQSLFFYPSYPDEVRGVFAVRTGKYKAHFFTQGSAHSDTTADPACHASSSL TAHEPPLLYDLSKDPGENYNLLGGVAGATPEVLQALKQLQLLKAQLDAAVTFGPSQVARG EDPALQICCHPGCTPRPACCHCPDPHA 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 | OTL-200 | Drug Info | Approved | Metachromatic leukodystrophy | [2] | |
| Clinical Trial Drug(s) | [+] 1 Clinical Trial Drugs | + | ||||
| 1 | HGT-1111 | Drug Info | Phase 2 | Metachromatic leukodystrophy | [1] | |
| Mode of Action | [+] 2 Modes of Action | + | ||||
| Replacement | [+] 1 Replacement drugs | + | ||||
| 1 | OTL-200 | Drug Info | [2] | |||
| Modulator | [+] 1 Modulator drugs | + | ||||
| 1 | HGT-1111 | 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: 4-Nitrocatechol sulfate | Ligand Info | |||||
| Structure Description | Crystal structure of an Arylsulfatase A mutant C69A | PDB:1E2S | ||||
| Method | X-ray diffraction | Resolution | 2.35 Å | Mutation | Yes | [3] |
| PDB Sequence |
RPPNIVLIFA
28 DDLGYGDLGC38 YGHPSSTTPN48 LDQLAAGGLR58 FTDFYVPVSL68 ATPSRAALLT 78 GRLPVRMGMY88 PGVLVPSSRG98 GLPLEEVTVA108 EVLAARGYLT118 GMAGKWHLGV 128 GPEGAFLPPH138 QGFHRFLGIP148 YSHDQGPCQN158 LTCFPPATPC168 DGGCDQGLVP 178 IPLLANLSVE188 AQPPWLPGLE198 ARYMAFAHDL208 MADAQRQDRP218 FFLYYASHHT 228 HYPQFSGQSF238 AERSGRGPFG248 DSLMELDAAV258 GTLMTAIGDL268 GLLEETLVIF 278 TADNGPETMR288 MSRGGCSGLL298 RCGKGTTYEG308 GVREPALAFW318 PGHIAPGVTH 328 ELASSLDLLP338 TLAALAGAPL348 PNVTLDGFDL358 SPLLLGTGKS368 PRQSLFFYPS 378 YPDEVRGVFA388 VRTGKYKAHF398 FTQGSAHSDT408 TADPACHASS418 SLTAHEPPLL 428 YDLSKDPGEN438 YNLLGATPEV452 LQALKQLQLL462 KAQLDAAVTF472 GPSQVARGED 482 PALQICCHPG492 CTPRPACCHC502 P
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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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| Sphingolipid metabolism | hsa00600 | Affiliated Target |
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| Class: Metabolism => Lipid metabolism | Pathway Hierarchy | ||
| Lysosome | hsa04142 | Affiliated Target |
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| Class: Cellular Processes => Transport and catabolism | Pathway Hierarchy | ||
| Degree | 3 | Degree centrality | 3.22E-04 | Betweenness centrality | 6.56E-04 |
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| Closeness centrality | 1.35E-01 | Radiality | 1.13E+01 | Clustering coefficient | 0.00E+00 |
| Neighborhood connectivity | 9.00E+00 | Topological coefficient | 5.33E-01 | Eccentricity | 13 |
| Download | Click to Download the Full PPI Network of This Target | ||||
| Target Affiliated Biological Pathways | Top | |||||
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| KEGG Pathway | [+] 2 KEGG Pathways | + | ||||
| 1 | Sphingolipid metabolism | |||||
| 2 | Lysosome | |||||
| Pathwhiz Pathway | [+] 1 Pathwhiz Pathways | + | ||||
| 1 | Sphingolipid Metabolism | |||||
| Reactome | [+] 1 Reactome Pathways | + | ||||
| 1 | Glycosphingolipid metabolism | |||||
| WikiPathways | [+] 1 WikiPathways | + | ||||
| 1 | Sphingolipid metabolism | |||||
| References | Top | |||||
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| REF 1 | ClinicalTrials.gov (NCT00681811) Open-Label Extension Study of Recombinant Human Arylsulfatase A (HGT-1111) in Late Infantile MLD. U.S. National Institutes of Health. | |||||
| REF 2 | Clinical pipeline report, company report or official report of Orchard Therapeutics. | |||||
| REF 3 | Crystal structure of an enzyme-substrate complex provides insight into the interaction between human arylsulfatase A and its substrates during catalysis. J Mol Biol. 2001 Jan 12;305(2):269-77. | |||||
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