Target Information
| Target General Information | Top | |||||
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| Target ID |
T78277
(Former ID: TTDI01982)
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| Target Name |
Asparaginase (ASRGL1)
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| Synonyms |
Lasparagine amidohydrolase; Isoaspartyl peptidase/Lasparaginase beta chain; Isoaspartyl peptidase/Lasparaginase; Isoaspartyl dipeptidase; Betaaspartylpeptidase; Asparaginaselike protein 1; ASRGL1
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| Gene Name |
ASRGL1
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| Target Type |
Successful target
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[1] | ||||
| Disease | [+] 1 Target-related Diseases | + | ||||
| 1 | Malignant haematopoietic neoplasm [ICD-11: 2B33] | |||||
| Function |
Has both L-asparaginase and beta-aspartyl peptidase activity. May be involved in the production of L-aspartate, which can act as an excitatory neurotransmitter in some brain regions. Is highly active with L-Asp beta-methyl ester. Besides, has catalytic activity toward beta-aspartyl dipeptides and their methyl esters, including beta-L-Asp-L-Phe, beta-L-Asp-L-Phe methyl ester (aspartame), beta-L-Asp-L-Ala, beta-L-Asp-L-Leu and beta-L- Asp-L-Lys. Does not have aspartylglucosaminidase activity and is inactive toward GlcNAc-L-Asn. Likewise, has no activity toward glutamine.
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| BioChemical Class |
Peptidase
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| UniProt ID | ||||||
| EC Number |
EC 3.4.19.5
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| Sequence |
MNPIVVVHGGGAGPISKDRKERVHQGMVRAATVGYGILREGGSAVDAVEGAVVALEDDPE
FNAGCGSVLNTNGEVEMDASIMDGKDLSAGAVSAVQCIANPIKLARLVMEKTPHCFLTDQ GAAQFAAAMGVPEIPGEKLVTERNKKRLEKEKHEKGAQKTDCQKNLGTVGAVALDCKGNV AYATSTGGIVNKMVGRVGDSPCLGAGGYADNDIGAVSTTGHGESILKVNLARLTLFHIEQ GKTVEEAADLSLGYMKSRVKGLGGLIVVSKTGDWVAKWTSTSMPWAAAKDGKLHFGIDPD DTTITDLP 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 | Calaspargase pegol | Drug Info | Approved | Acute lymphocytic leukaemia | [1] | |
| Clinical Trial Drug(s) | [+] 1 Clinical Trial Drugs | + | ||||
| 1 | GRASPA | Drug Info | Phase 3 | Acute lymphoblastic leukaemia | [2] | |
| Mode of Action | [+] 2 Modes of Action | + | ||||
| Inhibitor | [+] 1 Inhibitor drugs | + | ||||
| 1 | Calaspargase pegol | Drug Info | [1] | |||
| Modulator | [+] 1 Modulator drugs | + | ||||
| 1 | GRASPA | Drug Info | [3] | |||
| 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: L-aspartic acid | Ligand Info | |||||
| Structure Description | Crystal structure of human L-asparaginase protein with covalently linked substrate L-asparagine | PDB:4O0H | ||||
| Method | X-ray diffraction | Resolution | 1.97 Å | Mutation | No | [4] |
| PDB Sequence |
HMNPIVVVHG
9 GGAGPISKDR19 KERVHQGMVR29 AATVGYGILR39 EGGSAVDAVE49 GAVVALEDDP 59 EFNAGCGSVL69 NTNGEVEMDA79 SIMDGKDLSA89 GAVSAVQCIA99 NPIKLARLVM 109 EKTPHCFLTD119 QGAAQFAAAM129 GVPEIPGEKL139 VTERNKKRLE149 KEKHTVGAVA 173 LDCKGNVAYA183 TSTGGIVNKM193 VGRVGDSPCL203 GAGGYADNDI213 GAVSTTGHGE 223 SILKVNLARL233 TLFHIEQGKT243 VEEAADLSLG253 YMKSRVKGLG263 GLIVVSKTGD 273 WVAKWTSTSM283 PWAAAKDGKL293 HFGIDPDDTT303 ITDLP
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| Ligand Name: L-aspartic acid | Ligand Info | |||||
| Structure Description | Crystal structure of partially-cleaved human l-asparaginase protein in complex with l-aspartate | PDB:4PVR | ||||
| Method | X-ray diffraction | Resolution | 1.75 Å | Mutation | No | [5] |
| PDB Sequence |
HMNPIVVVHG
9 GGAGPISKDR19 KERVHQGMVR29 AATVGYGILR39 EGGSAVDAVE49 GAVVALEDDP 59 EFNAGCGSVL69 NTNGEVEMDA79 SIMDGKDLSA89 GAVSAVQCIA99 NPIKLARLVM 109 EKTPHCFLTD119 QGAAQFAAAM129 GVPEIPGEKL139 VTERNKKRLE149 KEKHNLGTVG 170 AVALDCKGNV180 AYATSTGGIV190 NKMVGRVGDS200 PCLGAGGYAD210 NDIGAVSTTG 220 HGESILKVNL230 ARLTLFHIEQ240 GKTVEEAADL250 SLGYMKSRVK260 GLGGLIVVSK 270 TGDWVAKWTS280 TSMPWAAAKD290 GKLHFGIDPD300 DTTITDLP
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| Click to View More Binding Site Information of This Target and Ligand Pair | ||||||
| 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).
Human Similarity Proteins
Human Tissue Distribution
Human Pathway Affiliation
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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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| Alanine, aspartate and glutamate metabolism | hsa00250 | Affiliated Target |
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| Class: Metabolism => Amino acid metabolism | Pathway Hierarchy | ||
| Target Affiliated Biological Pathways | Top | |||||
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| BioCyc | [+] 1 BioCyc Pathways | + | ||||
| 1 | Asparagine degradation | |||||
| Pathwhiz Pathway | [+] 2 Pathwhiz Pathways | + | ||||
| 1 | Aspartate Metabolism | |||||
| 2 | Ammonia Recycling | |||||
| References | Top | |||||
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| REF 1 | Pharmacokinetic and pharmacodynamic properties of calaspargase pegol Escherichia coli L-asparaginase in the treatment of patients with acute lymphoblastic leukemia: results from Children's Oncology Group Study AALL07P4. J Clin Oncol. 2014 Dec 1;32(34):3874-82. | |||||
| REF 2 | ClinicalTrials.gov (NCT01518517) GRASPA (Erythrocytes Encapsulating L-asparaginase) in Patients With Relapse of Acute Lymphoblastic Leukemia (GRASPIVOTALL). U.S. National Institutes of Health. | |||||
| REF 3 | l-asparaginase loaded red blood cells in refractory or relapsing acute lymphoblastic leukaemia in children and adults: results of the GRASPALL 2005-01 randomized trial. Br J Haematol. 2011 Apr;153(1):58-65. | |||||
| REF 4 | Elucidation of the specific function of the conserved threonine triad responsible for human L-asparaginase autocleavage and substrate hydrolysis. J Mol Biol. 2014 Jun 26;426(13):2471-85. | |||||
| REF 5 | Structures of apo and product-bound human L-asparaginase: insights into the mechanism of autoproteolysis and substrate hydrolysis. Biochemistry. 2012 Aug 28;51(34):6816-26. | |||||
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