Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTNQCHC6)

• DOT Name: ADP-ribose glycohydrolase MACROD2 (MACROD2)
• Synonyms: MACRO domain-containing protein 2; O-acetyl-ADP-ribose deacetylase MACROD2; EC 3.5.1.-; hydrolase MACROD2; EC 3.2.2.-; hydrolase MACROD2; EC 3.2.2.-
• Gene Name: MACROD2
• Related Disease:
  Advanced cancer
  Autism spectrum disorder
  Colon cancer
  Colon carcinoma
  Colorectal carcinoma
  Crohn disease
  Drug dependence
  Epstein barr virus infection
  High blood pressure
  Intellectual disability
  Liver cancer
  Mental disorder
  Obesity
  Pervasive developmental disorder
  Substance abuse
  Substance dependence
  Acute myelogenous leukaemia
  Autism
  Bipolar disorder
  HIV infectious disease
  Kabuki syndrome
  Neurodevelopmental disorder
• UniProt ID: MACD2_HUMAN
• PDB ID: 4IQY; 6Y4Y; 6Y4Z; 6Y73
• EC Number: 3.2.2.-; 3.5.1.-
• Pfam ID: PF01661
• Sequence:
  MYPSNKKKKVWREEKERLLKMTLEERRKEYLRDYIPLNSILSWKEEMKGKGQNDEENTQE
  TSQVKKSLTEKVSLYRGDITLLEVDAIVNAANASLLGGGGVDGCIHRAAGPCLLAECRNL
  NGCDTGHAKITCGYDLPAKYVIHTVGPIARGHINGSHKEDLANCYKSSLKLVKENNIRSV
  AFPCISTGIYGFPNEPAAVIALNTIKEWLAKNHHEVDRIIFCVFLEVDFKIYKKKMNEFF
  SVDDNNEEEEDVEMKEDSDENGPEEKQSVEEMEEQSQDADGVNTVTVPGPASEEAVEDCK
  DEDFAKDENITKGGEVTDHSVRDQDHPDGQENDSTKNEIKIETESQSSYMETEELSSNQE
  DAVIVEQPEVIPLTEDQEEKEGEKAPGEDTPRMPGKSEGSSDLENTPGPDAGAQDEAKEQ
  RNGTK
• Function: Removes ADP-ribose from aspartate and glutamate residues in proteins bearing a single ADP-ribose moiety. Inactive towards proteins bearing poly-ADP-ribose. Deacetylates O-acetyl-ADP ribose, a signaling molecule generated by the deacetylation of acetylated lysine residues in histones and other proteins.

Molecular Interaction Atlas (MIA) of This DOT

22 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Genetic Variation	[1]
Autism spectrum disorder	DISXK8NV	Strong	Genetic Variation	[2]
Colon cancer	DISVC52G	Strong	Altered Expression	[3]
Colon carcinoma	DISJYKUO	Strong	Altered Expression	[3]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[4]
Crohn disease	DIS2C5Q8	Strong	Genetic Variation	[5]
Drug dependence	DIS9IXRC	Strong	Biomarker	[6]
Epstein barr virus infection	DISOO0WT	Strong	Genetic Variation	[7]
High blood pressure	DISY2OHH	Strong	Genetic Variation	[8]
Intellectual disability	DISMBNXP	Strong	Biomarker	[1]
Liver cancer	DISDE4BI	Strong	Biomarker	[9]
Mental disorder	DIS3J5R8	Strong	Genetic Variation	[1]
Obesity	DIS47Y1K	Strong	Genetic Variation	[1]
Pervasive developmental disorder	DIS51975	Strong	Genetic Variation	[10]
Substance abuse	DIS327VW	Strong	Biomarker	[6]
Substance dependence	DISDRAAR	Strong	Biomarker	[6]
Acute myelogenous leukaemia	DISCSPTN	moderate	Genetic Variation	[11]
Autism	DISV4V1Z	moderate	Genetic Variation	[12]
Bipolar disorder	DISAM7J2	moderate	Genetic Variation	[13]
HIV infectious disease	DISO97HC	moderate	Genetic Variation	[14]
Kabuki syndrome	DISZN97H	Limited	Biomarker	[1]
Neurodevelopmental disorder	DIS372XH	Limited	Biomarker	[15]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of ADP-ribose glycohydrolase MACROD2 (MACROD2).	[16]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of ADP-ribose glycohydrolase MACROD2 (MACROD2).	[23]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of ADP-ribose glycohydrolase MACROD2 (MACROD2).	[17]
Acetaminophen	DMUIE76	Approved	Acetaminophen affects the expression of ADP-ribose glycohydrolase MACROD2 (MACROD2).	[18]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of ADP-ribose glycohydrolase MACROD2 (MACROD2).	[19]
Panobinostat	DM58WKG	Approved	Panobinostat decreases the expression of ADP-ribose glycohydrolase MACROD2 (MACROD2).	[20]
Malathion	DMXZ84M	Approved	Malathion decreases the expression of ADP-ribose glycohydrolase MACROD2 (MACROD2).	[21]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of ADP-ribose glycohydrolase MACROD2 (MACROD2).	[20]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of ADP-ribose glycohydrolase MACROD2 (MACROD2).	[22]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of ADP-ribose glycohydrolase MACROD2 (MACROD2).	[24]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of ADP-ribose glycohydrolase MACROD2 (MACROD2).	[25]

References

• [1] Mono-ADP-Ribosylhydrolase MACROD2 Is Dispensable for Murine Responses to Metabolic and Genotoxic Insults.Front Genet. 2018 Dec 12;9:654. doi: 10.3389/fgene.2018.00654. eCollection 2018.
• [2] The Long Noncoding RNA RPS10P2-AS1 Is Implicated in Autism Spectrum Disorder Risk and Modulates Gene Expression in Human Neuronal Progenitor Cells.Front Genet. 2019 Oct 15;10:970. doi: 10.3389/fgene.2019.00970. eCollection 2019.
• [3] MACROD2 expression predicts response to 5-FU-based chemotherapy in stage III colon cancer.Oncotarget. 2018 Jun 29;9(50):29445-29452. doi: 10.18632/oncotarget.25655. eCollection 2018 Jun 29.
• [4] High Prevalence and Clinical Relevance of Genes Affected by Chromosomal Breaks in Colorectal Cancer.PLoS One. 2015 Sep 16;10(9):e0138141. doi: 10.1371/journal.pone.0138141. eCollection 2015.
• [5] A genome-wide association study on a southern European population identifies a new Crohn's disease susceptibility locus at RBX1-EP300.Gut. 2013 Oct;62(10):1440-5. doi: 10.1136/gutjnl-2012-302865. Epub 2012 Aug 30.
• [6] Genome wide association for addiction: replicated results and comparisons of two analytic approaches.PLoS One. 2010 Jan 21;5(1):e8832. doi: 10.1371/journal.pone.0008832.
• [7] Genetic factors affecting EBV copy number in lymphoblastoid cell lines derived from the 1000 Genome Project samples.PLoS One. 2017 Jun 27;12(6):e0179446. doi: 10.1371/journal.pone.0179446. eCollection 2017.
• [8] Two-marker association tests yield new disease associations for coronary artery disease and hypertension.Hum Genet. 2011 Dec;130(6):725-33. doi: 10.1007/s00439-011-1009-6. Epub 2011 May 28.
• [9] Whole-genome mutational landscape and characterization of noncoding and structural mutations in liver cancer.Nat Genet. 2016 May;48(5):500-9. doi: 10.1038/ng.3547. Epub 2016 Apr 11.
• [10] No association between a common single nucleotide polymorphism, rs4141463, in the MACROD2 gene and autism spectrum disorder.Am J Med Genet B Neuropsychiatr Genet. 2011 Sep;156B(6):633-9. doi: 10.1002/ajmg.b.31201. Epub 2011 Jun 8.
• [11] Genome-wide haplotype association study identify the FGFR2 gene as a risk gene for acute myeloid leukemia.Oncotarget. 2017 Jan 31;8(5):7891-7899. doi: 10.18632/oncotarget.13631.
• [12] Replication of previous GWAS hits suggests the association between rs4307059 near MSNP1AS and autism in a Chinese Han population.Prog Neuropsychopharmacol Biol Psychiatry. 2019 Jun 8;92:194-198. doi: 10.1016/j.pnpbp.2018.12.016. Epub 2019 Jan 3.
• [13] Genome-wide association study meta-analysis of European and Asian-ancestry samples identifies three novel loci associated with bipolar disorder.Mol Psychiatry. 2013 Feb;18(2):195-205. doi: 10.1038/mp.2011.157. Epub 2011 Dec 20.
• [14] Genome-wide admixture and association study of subclinical atherosclerosis in the Women's Interagency HIV Study (WIHS).PLoS One. 2017 Dec 4;12(12):e0188725. doi: 10.1371/journal.pone.0188725. eCollection 2017.
• [15] Biochemical and Morphological Characterization of a Neurodevelopmental Disorder-Related Mono-ADP-Ribosylhydrolase, MACRO Domain Containing 2.Dev Neurosci. 2018;40(3):278-287. doi: 10.1159/000492271. Epub 2018 Sep 18.
• [16] 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.
• [17] 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.
• [18] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [19] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [20] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [21] Exposure to Insecticides Modifies Gene Expression and DNA Methylation in Hematopoietic Tissues In Vitro. Int J Mol Sci. 2023 Mar 26;24(7):6259. doi: 10.3390/ijms24076259.
• [22] Identification by automated screening of a small molecule that selectively eliminates neural stem cells derived from hESCs but not dopamine neurons. PLoS One. 2009 Sep 23;4(9):e7155.
• [23] 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.
• [24] 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.
• [25] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.