Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTNGNRBA)

• DOT Name: Isoaspartyl peptidase/L-asparaginase (ASRGL1)
• Synonyms: EC 3.4.19.5; EC 3.5.1.1; Asparaginase-like protein 1; Beta-aspartyl-peptidase; Isoaspartyl dipeptidase; L-asparagine amidohydrolase
• Gene Name: ASRGL1
• Related Disease: Inherited retinal dystrophy
• UniProt ID: ASGL1_HUMAN
• PDB ID: 3TKJ; 4ET0; 4O0C; 4O0D; 4O0E; 4O0F; 4O0G; 4O0H; 4OSX; 4OSY; 4PVP; 4PVQ; 4PVR; 4PVS; 4ZM9
• EC Number: 3.4.19.5; 3.5.1.1
• Pfam ID: PF01112
• Sequence:
  MNPIVVVHGGGAGPISKDRKERVHQGMVRAATVGYGILREGGSAVDAVEGAVVALEDDPE
  FNAGCGSVLNTNGEVEMDASIMDGKDLSAGAVSAVQCIANPIKLARLVMEKTPHCFLTDQ
  GAAQFAAAMGVPEIPGEKLVTERNKKRLEKEKHEKGAQKTDCQKNLGTVGAVALDCKGNV
  AYATSTGGIVNKMVGRVGDSPCLGAGGYADNDIGAVSTTGHGESILKVNLARLTLFHIEQ
  GKTVEEAADLSLGYMKSRVKGLGGLIVVSKTGDWVAKWTSTSMPWAAAKDGKLHFGIDPD
  DTTITDLP
• 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.
• Tissue Specificity: Expressed in brain, kidney, testis and tissues of the gastrointestinal tract. Present in sperm (at protein level). Over-expressed in uterine, mammary, prostatic and ovarian carcinoma.
• KEGG Pathway:
  Alanine, aspartate and glutamate metabolism (hsa00250)
  Metabolic pathways (hsa01100)
• Reactome Pathway: Phenylalanine metabolism (R-HSA-8964208)
• BioCyc Pathway: MetaCyc:HS08648-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Inherited retinal dystrophy	DISGGL77	Limited	Autosomal recessive	[1]

12 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Isoaspartyl peptidase/L-asparaginase (ASRGL1).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Isoaspartyl peptidase/L-asparaginase (ASRGL1).	[3]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Isoaspartyl peptidase/L-asparaginase (ASRGL1).	[4]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Isoaspartyl peptidase/L-asparaginase (ASRGL1).	[5]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Isoaspartyl peptidase/L-asparaginase (ASRGL1).	[6]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Isoaspartyl peptidase/L-asparaginase (ASRGL1).	[6]
Progesterone	DMUY35B	Approved	Progesterone decreases the expression of Isoaspartyl peptidase/L-asparaginase (ASRGL1).	[7]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol increases the expression of Isoaspartyl peptidase/L-asparaginase (ASRGL1).	[8]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Isoaspartyl peptidase/L-asparaginase (ASRGL1).	[9]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Isoaspartyl peptidase/L-asparaginase (ASRGL1).	[8]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Isoaspartyl peptidase/L-asparaginase (ASRGL1).	[11]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Isoaspartyl peptidase/L-asparaginase (ASRGL1).	[12]

1 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Isoaspartyl peptidase/L-asparaginase (ASRGL1).	[10]

References

• [1] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [2] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [3] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [4] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [5] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [6] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [7] Endometrial receptivity is affected in women with high circulating progesterone levels at the end of the follicular phase: a functional genomics analysis. Hum Reprod. 2011 Jul;26(7):1813-25.
• [8] Gene expression profiling in Ishikawa cells: a fingerprint for estrogen active compounds. Toxicol Appl Pharmacol. 2009 Apr 1;236(1):85-96.
• [9] LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
• [10] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [11] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [12] Comprehensive analysis of transcriptomic changes induced by low and high doses of bisphenol A in HepG2 spheroids in vitro and rat liver in vivo. Environ Res. 2019 Jun;173:124-134. doi: 10.1016/j.envres.2019.03.035. Epub 2019 Mar 18.