Target Information
| Target General Information | Top | |||||
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| Target ID |
T19567
(Former ID: TTDI02633)
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| Target Name |
Beta-N-acetylhexosaminidase (OGA)
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| Synonyms |
OGA; Nuclear cytoplasmic OGlcNAcase and acetyltransferase; Meningiomaexpressed antigen 5; MGEA5; Histone acetyltransferase; Bifunctional protein NCOAT
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| Gene Name |
MGEA5
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| Target Type |
Clinical trial target
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[1] | ||||
| Disease | [+] 2 Target-related Diseases | + | ||||
| 1 | Alzheimer disease [ICD-11: 8A20] | |||||
| 2 | Parkinsonism [ICD-11: 8A00] | |||||
| Function |
Isoform 3: Cleaves GlcNAc but not GalNAc from O- glycosylated proteins. Can use p-nitrophenyl-beta-GlcNAc as substrate but not p-nitrophenyl-beta-GalNAc or p-nitrophenyl- alpha-GlcNAc (in vitro), but has about six times lower specific activity than isoform1. {ECO:0000269|PubMed:20673219}.
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| BioChemical Class |
Glycosylase
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| UniProt ID | ||||||
| EC Number |
EC 3.2.1.169
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| Sequence |
MVQKESQATLEERESELSSNPAASAGASLEPPAAPAPGEDNPAGAGGAAVAGAAGGARRF
LCGVVEGFYGRPWVMEQRKELFRRLQKWELNTYLYAPKDDYKHRMFWREMYSVEEAEQLM TLISAAREYEIEFIYAISPGLDITFSNPKEVSTLKRKLDQVSQFGCRSFALLFDDIDHNM CAADKEVFSSFAHAQVSITNEIYQYLGEPETFLFCPTEYCGTFCYPNVSQSPYLRTVGEK LLPGIEVLWTGPKVVSKEIPVESIEEVSKIIKRAPVIWDNIHANDYDQKRLFLGPYKGRS TELIPRLKGVLTNPNCEFEANYVAIHTLATWYKSNMNGVRKDVVMTDSEDSTVSIQIKLE NEGSDEDIETDVLYSPQMALKLALTEWLQEFGVPHQYSSRQVAHSGAKASVVDGTPLVAA PSLNATTVVTTVYQEPIMSQGAALSGEPTTLTKEEEKKQPDEEPMDMVVEKQEETDHKND NQILSEIVEAKMAEELKPMDTDKESIAESKSPEMSMQEDCISDIAPMQTDEQTNKEQFVP GPNEKPLYTAEPVTLEDLQLLADLFYLPYEHGPKGAQMLREFQWLRANSSVVSVNCKGKD SEKIEEWRSRAAKFEEMCGLVMGMFTRLSNCANRTILYDMYSYVWDIKSIMSMVKSFVQW LGCRSHSSAQFLIGDQEPWAFRGGLAGEFQRLLPIDGANDLFFQPPPLTPTSKVYTIRPY FPKDEASVYKICREMYDDGVGLPFQSQPDLIGDKLVGGLLSLSLDYCFVLEDEDGICGYA LGTVDVTPFIKKCKISWIPFMQEKYTKPNGDKELSEAEKIMLSFHEEQEVLPETFLANFP SLIKMDIHKKVTDPSVAKSMMACLLSSLKANGSRGAFCEVRPDDKRILEFYSKLGCFEIA KMEGFPKDVVILGRSL 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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| Clinical Trial Drug(s) | [+] 5 Clinical Trial Drugs | + | ||||
| 1 | LY3372689 | Drug Info | Phase 2 | Alzheimer disease | [2] | |
| 2 | ASN51 | Drug Info | Phase 1 | Alzheimer disease | [3] | |
| 3 | BIIB113 | Drug Info | Phase 1 | Alzheimer disease | [4] | |
| 4 | MK 8719 | Drug Info | Phase 1 | Progressive supranuclear palsy | [1] | |
| 5 | MK-8719 | Drug Info | Phase 1 | Progressive supranuclear palsy | [5] | |
| Mode of Action | [+] 1 Modes of Action | + | ||||
| Inhibitor | [+] 5 Inhibitor drugs | + | ||||
| 1 | LY3372689 | Drug Info | [2] | |||
| 2 | ASN51 | Drug Info | [6] | |||
| 3 | BIIB113 | Drug Info | [4] | |||
| 4 | MK 8719 | Drug Info | [1] | |||
| 5 | MK-8719 | 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: MK-8719 | Ligand Info | |||||
| Structure Description | Crystal structure of the core catalytic domain of human O-GlcNAcase bound to MK-8719 | PDB:6PM9 | ||||
| Method | X-ray diffraction | Resolution | 2.86 Å | Mutation | No | [5] |
| PDB Sequence |
RFLCGVVEGF
68 YGRPWVMEQR78 KELFRRLQKW88 ELNTYLYAPK98 DDYKHRMFWR108 EMYSVEEAEQ 118 LMTLISAARE128 YEIEFIYAIS138 PGLDITFSNP148 KEVSTLKRKL158 DQVSQFGCRS 168 FALLFDDIDH178 NMCAADKEVF188 SSFAHAQVSI198 TNEIYQYLGE208 PETFLFCPTE 218 YCGTFCYPNV228 SQSPYLRTVG238 EKLLPGIEVL248 WTGPKVVSKE258 IPVESIEEVS 268 KIIKRAPVIW278 DNIHANDYDQ288 KRLFLGPYKG298 RSTELIPRLK308 GVLTNPNCEF 318 EANYVAIHTL328 ATWYKSNMNG338 VRDVLYSPQM378 ALKLALTEWL388 QEFGVPHQY |
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| Ligand Name: 2-[(2~{r},3~{s},4~{r},5~{r})-5-(Hydroxymethyl)-3,4-Bis(Oxidanyl)-1-[3-[3-(Trifluoromethyl)phenyl]propyl]pyrrolidin-2-Yl]-~{n}-Methyl-Ethanamide | Ligand Info | |||||
| Structure Description | Structure of human O-GlcNAc hydrolase with new iminocyclitol type inhibitor | PDB:5M7U | ||||
| Method | X-ray diffraction | Resolution | 2.30 Å | Mutation | No | [7] |
| PDB Sequence |
RFLCGVVEGF
68 YGRPWVMEQR78 KELFRRLQKW88 ELNTYLYAPK98 DDYKHRMFWR108 EMYSVEEAEQ 118 LMTLISAARE128 YEIEFIYAIS138 PGLDITFSNP148 KEVSTLKRKL158 DQVSQFGCRS 168 FALLFDDIDH178 NMCAADKEVF188 SSFAHAQVSI198 TNEIYQYLGE208 PETFLFCPTE 218 YCGTFCYPNV228 SQSPYLRTVG238 EKLLPGIEVL248 WTGPKVVSKE258 IPVESIEEVS 268 KIIKRAPVIW278 DNIHANDYDQ288 KRLFLGPYKG298 RSTELIPRLK308 GVLTNPNCEF 318 EANYVAIHTL328 ATWYKSNMND371 VLYSPQMALK381 LALTEWLQEF391 GVPHQFVPGP 542 NEKPLYTAEP552 VTLEDLQLLA562 DLFYLPYEHG572 PKGAQMLREF582 QWLRANSSVV 592 SSEKIEEWRS609 RAAKFEEMCG619 LVMGMFTRLS629 NCANRTILYD639 MYSYVWDIKS 649 IMSMVKSFVQ659 WLGCLIGDQE677 PWAFRGGLAG687 EFQRLLPI
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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).
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
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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| Degree | 1 | Degree centrality | 1.07E-04 | Betweenness centrality | 0.00E+00 |
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| Closeness centrality | 1.69E-01 | Radiality | 1.27E+01 | Clustering coefficient | 0.00E+00 |
| Neighborhood connectivity | 7.00E+00 | Topological coefficient | 1.00E+00 | 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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| Target Poor or Non Binders | Top | |||||
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| Target Poor or Non Binders | ||||||
| References | Top | |||||
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| REF 1 | Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA) | |||||
| REF 2 | ClinicalTrials.gov (NCT05063539) Assessment of Safety, Tolerability, and Efficacy of LY3372689 in Early Symptomatic Alzheimer's Disease. U.S.National Institutes of Health. | |||||
| REF 3 | ClinicalTrials.gov (NCT04759365) A Randomized, Double-Blind, Placebo-Controlled, Phase 1 Safety, Tolerability, Pharmacokinetics and Pharmacodynamics Study of Oral ASN51 in Healthy Young Adult and Elderly Subjects and Elderly Subjects With Alzheimer's Disease. U.S.National Institutes of Health. | |||||
| REF 4 | ClinicalTrials.gov (NCT05195008) A Phase 1 Randomized, Blinded, Placebo-Controlled, Single- and Multiple-Ascending Dose Study to Evaluate the Safety, Tolerability, and Pharmacokinetics, With an Open-Label Target Occupancy Study of BIIB113 in Healthy Participants. U.S.National Institutes of Health. | |||||
| REF 5 | Discovery of MK-8719, a Potent O-GlcNAcase Inhibitor as a Potential Treatment for Tauopathies. J Med Chem. 2019 Nov 27;62(22):10062-10097. | |||||
| REF 6 | Clinical pipeline report, company report or official report of Asceneuron | |||||
| REF 7 | Structural and functional insight into human O-GlcNAcase. Nat Chem Biol. 2017 Jun;13(6):610-612. | |||||
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