Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTI2NGQR)

DOT Name	Argininosuccinate lyase (ASL)
Synonyms	ASAL; EC 4.3.2.1; Arginosuccinase
Gene Name	ASL
Related Disease	Argininosuccinic aciduria ( ) Breast carcinoma ( ) Glioblastoma multiforme ( ) Pulmonary disease ( ) Adult glioblastoma ( ) Advanced cancer ( ) Alzheimer disease ( ) Androgen insensitivity syndrome ( ) Arginase 1 deficiency ( ) Autism ( ) Breast cancer ( ) Carbamoyl phosphate synthetase I deficiency disease ( ) Central nervous system lymphoma ( ) Cognitive impairment ( ) Colon cancer ( ) Colon carcinoma ( ) Colorectal carcinoma ( ) Glioma ( ) Hepatitis B virus infection ( ) Liver failure ( ) Lung cancer ( ) Lung carcinoma ( ) Meningioma ( ) Moyamoya disease ( ) Neoplasm ( ) Tuberculosis ( ) Carcinoma of liver and intrahepatic biliary tract ( ) Hepatocellular carcinoma ( ) Liver cancer ( ) Intellectual disability ( ) Urea cycle disorder ( )
UniProt ID	ARLY_HUMAN
3D Structure	Download 2D Sequence (FASTA) Download 3D Structure (PDB) Download
PDB ID	1AOS; 1K62
EC Number	4.3.2.1
Pfam ID	PF14698 ; PF00206
Sequence	MASESGKLWGGRFVGAVDPIMEKFNASIAYDRHLWEVDVQGSKAYSRGLEKAGLLTKAEM DQILHGLDKVAEEWAQGTFKLNSNDEDIHTANERRLKELIGATAGKLHTGRSRNDQVVTD LRLWMRQTCSTLSGLLWELIRTMVDRAEAERDVLFPGYTHLQRAQPIRWSHWILSHAVAL TRDSERLLEVRKRINVLPLGSGAIAGNPLGVDRELLRAELNFGAITLNSMDATSERDFVA EFLFWASLCMTHLSRMAEDLILYCTKEFSFVQLSDAYSTGSSLMPQKKNPDSLELIRSKA GRVFGRCAGLLMTLKGLPSTYNKDLQEDKEAVFEVSDTMSAVLQVATGVISTLQIHQENM GQALSPDMLATDLAYYLVRKGMPFRQAHEASGKAVFMAETKGVALNQLSLQELQTISPLF SGDVICVWDYGHSVEQYGALGGTARSSVDWQIRQVRALLQAQQA
Function	Catalyzes the reversible cleavage of L-argininosuccinate to fumarate and L-arginine, an intermediate step reaction in the urea cycle mostly providing for hepatic nitrogen detoxification into excretable urea as well as de novo L-arginine synthesis in nonhepatic tissues. Essential regulator of intracellular and extracellular L-arginine pools. As part of citrulline-nitric oxide cycle, forms tissue-specific multiprotein complexes with argininosuccinate synthase ASS1, transport protein SLC7A1 and nitric oxide synthase NOS1, NOS2 or NOS3, allowing for cell-autonomous L-arginine synthesis while channeling extracellular L-arginine to nitric oxide synthesis pathway.
KEGG Pathway	Arginine biosynthesis (hsa00220 ) Alanine, aspartate and glutamate metabolism (hsa00250 ) Metabolic pathways (hsa01100 ) Biosynthesis of amino acids (hsa01230 )
Reactome Pathway	Urea cycle (R-HSA-70635 )
BioCyc Pathway	MetaCyc:HS10034-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

31 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance
Argininosuccinic aciduria	DIS141BY	Definitive	Autosomal recessive	[1]
Breast carcinoma	DIS2UE88	Definitive	Altered Expression	[2]
Glioblastoma multiforme	DISK8246	Definitive	Biomarker	[3]
Pulmonary disease	DIS6060I	Definitive	Biomarker	[4]
Adult glioblastoma	DISVP4LU	Strong	Biomarker	[5]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[6]
Alzheimer disease	DISF8S70	Strong	Biomarker	[7]
Androgen insensitivity syndrome	DISUZBBO	Strong	Biomarker	[8]
Arginase 1 deficiency	DISAGUMY	Strong	Genetic Variation	[9]
Autism	DISV4V1Z	Strong	Genetic Variation	[10]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[2]
Carbamoyl phosphate synthetase I deficiency disease	DISSOMMH	Strong	Genetic Variation	[9]
Central nervous system lymphoma	DISBYQTA	Strong	Genetic Variation	[11]
Cognitive impairment	DISH2ERD	Strong	Genetic Variation	[12]
Colon cancer	DISVC52G	Strong	Altered Expression	[13]
Colon carcinoma	DISJYKUO	Strong	Altered Expression	[13]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[14]
Glioma	DIS5RPEH	Strong	Biomarker	[15]
Hepatitis B virus infection	DISLQ2XY	Strong	Altered Expression	[16]
Liver failure	DISLGEL6	Strong	Biomarker	[17]
Lung cancer	DISCM4YA	Strong	Biomarker	[4]
Lung carcinoma	DISTR26C	Strong	Biomarker	[4]
Meningioma	DISPT4TG	Strong	Biomarker	[18]
Moyamoya disease	DISO62CA	Strong	Biomarker	[19]
Neoplasm	DISZKGEW	Strong	Biomarker	[18]
Tuberculosis	DIS2YIMD	Strong	Biomarker	[20]
Carcinoma of liver and intrahepatic biliary tract	DIS8WA0W	moderate	Biomarker	[2]
Hepatocellular carcinoma	DIS0J828	moderate	Biomarker	[21]
Liver cancer	DISDE4BI	moderate	Biomarker	[2]
Intellectual disability	DISMBNXP	Limited	Genetic Variation	[22]
Urea cycle disorder	DIS5O5V0	Limited	Biomarker	[23]
------------------------------------------------------------------------------------


⏷ Show the Full List of 31 Disease(s)

Molecular Interaction Atlas (MIA)

MIA Detail

Jump to Detail Molecular Interaction Atlas of This DOT

15 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 Argininosuccinate lyase (ASL).	[24]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Argininosuccinate lyase (ASL).	[25]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Argininosuccinate lyase (ASL).	[26]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Argininosuccinate lyase (ASL).	[27]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Argininosuccinate lyase (ASL).	[28]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Argininosuccinate lyase (ASL).	[29]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Argininosuccinate lyase (ASL).	[30]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Argininosuccinate lyase (ASL).	[31]
Selenium	DM25CGV	Approved	Selenium increases the expression of Argininosuccinate lyase (ASL).	[32]
Aspirin	DM672AH	Approved	Aspirin decreases the expression of Argininosuccinate lyase (ASL).	[33]
Diclofenac	DMPIHLS	Approved	Diclofenac affects the expression of Argininosuccinate lyase (ASL).	[31]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Argininosuccinate lyase (ASL).	[34]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Argininosuccinate lyase (ASL).	[35]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Argininosuccinate lyase (ASL).	[36]
BRN-3548355	DM4KXT0	Investigative	BRN-3548355 increases the expression of Argininosuccinate lyase (ASL).	[37]
------------------------------------------------------------------------------------


⏷ Show the Full List of 15 Drug(s)

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	Argininosuccinate lyase is a potential therapeutic target in breast cancer.Oncol Rep. 2015 Dec;34(6):3131-9. doi: 10.3892/or.2015.4280. Epub 2015 Sep 16.
3	Arterial spin labeling perfusion-weighted imaging aids in prediction of molecular biomarkers and survival in glioblastomas.Eur Radiol. 2020 Feb;30(2):1202-1211. doi: 10.1007/s00330-019-06379-2. Epub 2019 Aug 29.
4	Deaf patient-provider communication and lung cancer screening: Health Information National Trends survey in American Sign Language (HINTS-ASL).Patient Educ Couns. 2018 Jul;101(7):1232-1239. doi: 10.1016/j.pec.2018.03.003. Epub 2018 Mar 5.
5	Epigenetic status of argininosuccinate synthetase and argininosuccinate lyase modulates autophagy and cell death in glioblastoma.Cell Death Dis. 2013 Jan 17;4(1):e458. doi: 10.1038/cddis.2012.197.
6	Attenuation of argininosuccinate lyase inhibits cancer growth via cyclin A2 and nitric oxide.Mol Cancer Ther. 2013 Nov;12(11):2505-16. doi: 10.1158/1535-7163.MCT-12-0863. Epub 2013 Aug 26.
7	Alzheimer Disease and Mild Cognitive Impairment: Integrated Pulsed Arterial Spin-Labeling MRI and (18)F-FDG PET.Radiology. 2018 Jul;288(1):198-206. doi: 10.1148/radiol.2018170575. Epub 2018 May 15.
8	Monitoring cerebral blood flow change through use of arterial spin labelling in acute ischaemic stroke patients after intra-arterial thrombectomy.Eur Radiol. 2018 Aug;28(8):3276-3284. doi: 10.1007/s00330-018-5319-0. Epub 2018 Feb 23.
9	Hereditary urea cycle diseases in Finland.Acta Paediatr. 2008 Oct;97(10):1412-9. doi: 10.1111/j.1651-2227.2008.00923.x. Epub 2008 Jul 9.
10	Two novel mutant human adenylosuccinate lyases (ASLs) associated with autism and characterization of the equivalent mutant Bacillus subtilis ASL.J Biol Chem. 2004 Dec 17;279(51):53789-97. doi: 10.1074/jbc.M409974200. Epub 2004 Oct 7.
11	Differentiation between primary CNS lymphoma and glioblastoma: qualitative and quantitative analysis using arterial spin labeling MR imaging.Eur Radiol. 2018 Sep;28(9):3801-3810. doi: 10.1007/s00330-018-5359-5. Epub 2018 Apr 4.
12	ASL Metabolically Regulates Tyrosine Hydroxylase in the Nucleus Locus Coeruleus.Cell Rep. 2019 Nov 19;29(8):2144-2153.e7. doi: 10.1016/j.celrep.2019.10.043.
13	Induction of Nitric-Oxide Metabolism in Enterocytes Alleviates Colitis and Inflammation-Associated Colon Cancer.Cell Rep. 2018 May 15;23(7):1962-1976. doi: 10.1016/j.celrep.2018.04.053.
14	Silencing of argininosuccinate lyase inhibits colorectal cancer formation.Oncol Rep. 2017 Jan;37(1):163-170. doi: 10.3892/or.2016.5221. Epub 2016 Nov 7.
15	KLF7 promotes polyamine biosynthesis and glioma development through transcriptionally activating ASL.Biochem Biophys Res Commun. 2019 Jun 18;514(1):51-57. doi: 10.1016/j.bbrc.2019.04.120. Epub 2019 Apr 21.
16	Clinical, biochemical, immunological and virological profiles of, and differential diagnosis between, patients with acute hepatitis B and chronic hepatitis B with acute flare.J Gastroenterol Hepatol. 2008 Nov;23(11):1728-33. doi: 10.1111/j.1440-1746.2008.05600.x. Epub 2008 Sep 24.
17	Messenger RNA profiles in liver injury and stress: a comparison of lethal and nonlethal rat models.Biochem Biophys Res Commun. 2002 Jan 11;290(1):518-25. doi: 10.1006/bbrc.2001.6216.
18	Arterial spin-labeling is useful for the diagnosis of residual or recurrent meningiomas.Eur Radiol. 2018 Oct;28(10):4334-4342. doi: 10.1007/s00330-018-5404-4. Epub 2018 Apr 13.
19	Cerebral Perfusion Territory Changes After Direct Revascularization Surgery in Moyamoya Disease: A Territory Arterial Spin Labeling Study.World Neurosurg. 2019 Feb;122:e1128-e1136. doi: 10.1016/j.wneu.2018.11.002. Epub 2018 Nov 14.
20	Crystal structure and biochemical study on argininosuccinate lyase from Mycobacterium tuberculosis.Biochem Biophys Res Commun. 2019 Feb 26;510(1):116-121. doi: 10.1016/j.bbrc.2019.01.061. Epub 2019 Jan 18.
21	Argininosuccinate lyase interacts with cyclin A2 in cytoplasm and modulates growth of liver tumor cells.Oncol Rep. 2017 Feb;37(2):969-978. doi: 10.3892/or.2016.5334. Epub 2016 Dec 23.
22	Expression, purification, and kinetic characterization of recombinant human adenylosuccinate lyase.J Biol Chem. 1993 Sep 15;268(26):19710-6.
23	Argininosuccinate neurotoxicity and prevention by creatine in argininosuccinate lyase deficiency: An in vitro study in rat three-dimensional organotypic brain cell cultures.J Inherit Metab Dis. 2019 Nov;42(6):1077-1087. doi: 10.1002/jimd.12090. Epub 2019 Apr 14.
24	Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
25	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.
26	The retinoid anticancer signal: mechanisms of target gene regulation. Br J Cancer. 2005 Aug 8;93(3):310-8. doi: 10.1038/sj.bjc.6602700.
27	Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
28	Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
29	Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
30	Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
31	Drug-induced endoplasmic reticulum and oxidative stress responses independently sensitize toward TNF-mediated hepatotoxicity. Toxicol Sci. 2014 Jul;140(1):144-59. doi: 10.1093/toxsci/kfu072. Epub 2014 Apr 20.
32	Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
33	Expression profile analysis of human peripheral blood mononuclear cells in response to aspirin. Arch Immunol Ther Exp (Warsz). 2005 Mar-Apr;53(2):151-8.
34	Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
35	Alternatives for the worse: Molecular insights into adverse effects of bisphenol a and substitutes during human adipocyte differentiation. Environ Int. 2021 Nov;156:106730. doi: 10.1016/j.envint.2021.106730. Epub 2021 Jun 27.
36	Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
37	Gene expression profiles in HPV-immortalized human cervical cells treated with the nicotine-derived carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone. Chem Biol Interact. 2009 Feb 12;177(3):173-80. doi: 10.1016/j.cbi.2008.10.051. Epub 2008 Nov 6.