Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTBS30JU)

• DOT Name: AMP deaminase 2 (AMPD2)
• Synonyms: EC 3.5.4.6; AMP deaminase isoform L
• Gene Name: AMPD2
• Related Disease:
  Metabolic disorder
  Pontocerebellar hypoplasia type 9
  Advanced cancer
  Corpus callosum, agenesis of
  Cystic fibrosis
  Fatty liver disease
  Glycogen storage disease V
  Hepatocellular carcinoma
  Isolated congenital microcephaly
  Neoplasm
  Pontocerebellar hypoplasia
  Systemic lupus erythematosus
  Stickler syndrome type 2
  Hereditary spastic paraplegia 63
• UniProt ID: AMPD2_HUMAN
• PDB ID: 4NO3; 4NO5; 8HU6; 8HUB
• EC Number: 3.5.4.6
• Pfam ID: PF19326
• Sequence:
  MASYPSGSGKPKAKYPFKKRASLQASTAAPEARGGLGAPPLQSARSLPGPAPCLKHFPLD
  LRTSMDGKCKEIAEELFTRSLAESELRSAPYEFPEESPIEQLEERRQRLERQISQDVKLE
  PDILLRAKQDFLKTDSDSDLQLYKEQGEGQGDRSLRERDVLEREFQRVTISGEEKCGVPF
  TDLLDAAKSVVRALFIREKYMALSLQSFCPTTRRYLQQLAEKPLETRTYEQGPDTPVSAD
  APVHPPALEQHPYEHCEPSTMPGDLGLGLRMVRGVVHVYTRREPDEHCSEVELPYPDLQE
  FVADVNVLMALIINGPIKSFCYRRLQYLSSKFQMHVLLNEMKELAAQKKVPHRDFYNIRK
  VDTHIHASSCMNQKHLLRFIKRAMKRHLEEIVHVEQGREQTLREVFESMNLTAYDLSVDT
  LDVHADRNTFHRFDKFNAKYNPIGESVLREIFIKTDNRVSGKYFAHIIKEVMSDLEESKY
  QNAELRLSIYGRSRDEWDKLARWAVMHRVHSPNVRWLVQVPRLFDVYRTKGQLANFQEML
  ENIFLPLFEATVHPASHPELHLFLEHVDGFDSVDDESKPENHVFNLESPLPEAWVEEDNP
  PYAYYLYYTFANMAMLNHLRRQRGFHTFVLRPHCGEAGPIHHLVSAFMLAENISHGLLLR
  KAPVLQYLYYLAQIGIAMSPLSNNSLFLSYHRNPLPEYLSRGLMVSLSTDDPLQFHFTKE
  PLMEEYSIATQVWKLSSCDMCELARNSVLMSGFSHKVKSHWLGPNYTKEGPEGNDIRRTN
  VPDIRVGYRYETLCQELALITQAVQSEMLETIPEEAGITMSPGPQ
• Function: AMP deaminase plays a critical role in energy metabolism. Catalyzes the deamination of AMP to IMP and plays an important role in the purine nucleotide cycle.
• Tissue Specificity: Highly expressed in cerebellum.
• KEGG Pathway:
  Purine metabolism (hsa00230)
  Metabolic pathways (hsa01100)
  Nucleotide metabolism (hsa01232)
  Cytoskeleton in muscle cells (hsa04820)
• Reactome Pathway: Purine salvage (R-HSA-74217)
• BioCyc Pathway: MetaCyc:HS04008-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

14 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Metabolic disorder	DIS71G5H	Definitive	Genetic Variation	[1]
Pontocerebellar hypoplasia type 9	DISMRCK2	Definitive	Autosomal recessive	[2]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[3]
Corpus callosum, agenesis of	DISO9P40	Strong	Genetic Variation	[4]
Cystic fibrosis	DIS2OK1Q	Strong	Biomarker	[5]
Fatty liver disease	DIS485QZ	Strong	Altered Expression	[6]
Glycogen storage disease V	DISJNC0O	Strong	Genetic Variation	[7]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[8]
Isolated congenital microcephaly	DISUXHZ6	Strong	Biomarker	[4]
Neoplasm	DISZKGEW	Strong	Altered Expression	[8]
Pontocerebellar hypoplasia	DISRICMU	Strong	Genetic Variation	[4]
Systemic lupus erythematosus	DISI1SZ7	Strong	Biomarker	[9]
Stickler syndrome type 2	DIS4AZNW	moderate	Genetic Variation	[10]
Hereditary spastic paraplegia 63	DIS9ZG6T	Supportive	Autosomal recessive	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of AMP deaminase 2 (AMPD2).	[12]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of AMP deaminase 2 (AMPD2).	[20]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of AMP deaminase 2 (AMPD2).	[23]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of AMP deaminase 2 (AMPD2).	[24]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of AMP deaminase 2 (AMPD2).	[23]
Hexadecanoic acid	DMWUXDZ	Investigative	Hexadecanoic acid decreases the phosphorylation of AMP deaminase 2 (AMPD2).	[25]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of AMP deaminase 2 (AMPD2).	[13]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of AMP deaminase 2 (AMPD2).	[14]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of AMP deaminase 2 (AMPD2).	[15]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of AMP deaminase 2 (AMPD2).	[16]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of AMP deaminase 2 (AMPD2).	[17]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil decreases the expression of AMP deaminase 2 (AMPD2).	[18]
Tofacitinib	DMBS370	Approved	Tofacitinib decreases the expression of AMP deaminase 2 (AMPD2).	[19]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of AMP deaminase 2 (AMPD2).	[15]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of AMP deaminase 2 (AMPD2).	[21]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of AMP deaminase 2 (AMPD2).	[22]

References

• [1] Molecular analysis of Spanish patients with AMP deaminase deficiency.Muscle Nerve. 2000 Aug;23(8):1175-8. doi: 10.1002/1097-4598(200008)23:8<1175::aid-mus3>3.0.co;2-m.
• [2] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [3] Amphiphilic polysaccharides as building blocks for self-assembled nanosystems: molecular design and application in cancer and inflammatory diseases.J Control Release. 2018 Feb 28;272:114-144. doi: 10.1016/j.jconrel.2017.12.033. Epub 2017 Dec 30.
• [4] Clinical and genetic spectrum of AMPD2-related pontocerebellar hypoplasia type 9.Eur J Hum Genet. 2018 May;26(5):695-708. doi: 10.1038/s41431-018-0098-2. Epub 2018 Feb 20.
• [5] Molecular Epidemiology of Mutations in Antimicrobial Resistance Loci of Pseudomonas aeruginosa Isolates from Airways of Cystic Fibrosis Patients.Antimicrob Agents Chemother. 2016 Oct 21;60(11):6726-6734. doi: 10.1128/AAC.00724-16. Print 2016 Nov.
• [6] Counteracting roles of AMP deaminase and AMP kinase in the development of fatty liver.PLoS One. 2012;7(11):e48801. doi: 10.1371/journal.pone.0048801. Epub 2012 Nov 9.
• [7] AMPD1 genotypes and exercise capacity in McArdle patients.Int J Sports Med. 2008 Apr;29(4):331-5. doi: 10.1055/s-2007-965358. Epub 2007 Aug 9.
• [8] Expression patterns of AMP-deaminase isozymes in human hepatocellular carcinoma (HCC).Mol Cell Biochem. 2008 Nov;318(1-2):1-5. doi: 10.1007/s11010-008-9773-x. Epub 2008 May 21.
• [9] NovelmiRNA-25 inhibits AMPD2 in peripheral blood mononuclear cells of patients with systemic lupus erythematosus and represents a promising novel biomarker.J Transl Med. 2018 Dec 22;16(1):370. doi: 10.1186/s12967-018-1739-5.
• [10] Homozygous variants in AMPD2 and COL11A1 lead to a complex phenotype of pontocerebellar hypoplasia type 9 and Stickler syndrome type 2.Am J Med Genet A. 2020 Mar;182(3):557-560. doi: 10.1002/ajmg.a.61452. Epub 2019 Dec 12.
• [11] Exome sequencing links corticospinal motor neuron disease to common neurodegenerative disorders. Science. 2014 Jan 31;343(6170):506-511. doi: 10.1126/science.1247363.
• [12] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [13] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [14] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [15] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
• [16] 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.
• [17] Integrated assessment by multiple gene expression analysis of quercetin bioactivity on anticancer-related mechanisms in colon cancer cells in vitro. Eur J Nutr. 2005 Mar;44(3):143-56. doi: 10.1007/s00394-004-0503-1. Epub 2004 Apr 30.
• [18] Expression profiling of nucleotide metabolism-related genes in human breast cancer cells after treatment with 5-fluorouracil. Cancer Invest. 2009 Jun;27(5):561-7.
• [19] Effects of tofacitinib on nucleic acid metabolism in human articular chondrocytes. Mod Rheumatol. 2015 Jul;25(4):522-7. doi: 10.3109/14397595.2014.995874. Epub 2015 Jan 13.
• [20] 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.
• [21] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.
• [22] 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.
• [23] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [24] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [25] Functional lipidomics: Palmitic acid impairs hepatocellular carcinoma development by modulating membrane fluidity and glucose metabolism. Hepatology. 2017 Aug;66(2):432-448. doi: 10.1002/hep.29033. Epub 2017 Jun 16.