Details of Drug Off-Target (DOT)

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

• DOT Name: ADP-ribose glycohydrolase MACROD1 (MACROD1)
• Synonyms: MACRO domain-containing protein 1; O-acetyl-ADP-ribose deacetylase MACROD1; EC 3.1.1.106; Protein LRP16; hydrolase MACROD1; EC 3.2.2.-; hydrolase MACROD1; EC 3.2.2.-
• Gene Name: MACROD1
• Related Disease:
  leukaemia
  Leukemia
  Metabolic disorder
  Advanced cancer
  Breast cancer
  Breast carcinoma
  Cardiovascular disease
  Colorectal carcinoma
  Endometrial cancer
  Endometrial carcinoma
  Gout
  Monocytic leukemia
  Pancreatic cancer
  Bipolar disorder
  Hepatocellular carcinoma
  Neoplasm
• UniProt ID: MACD1_HUMAN
• PDB ID: 2X47; 6LH4
• EC Number: 3.1.1.106; 3.2.2.-
• Pfam ID: PF01661
• Sequence:
  MSLQSRLSGRLAQLRAAGQLLVPPRPRPGHLAGATRTRSSTCGPPAFLGVFGRRARTSAG
  VGAWGAAAVGRTAGVRTWAPLAMAAKVDLSTSTDWKEAKSFLKGLSDKQREEHYFCKDFV
  RLKKIPTWKEMAKGVAVKVEEPRYKKDKQLNEKISLLRSDITKLEVDAIVNAANSSLLGG
  GGVDGCIHRAAGPLLTDECRTLQSCKTGKAKITGGYRLPAKYVIHTVGPIAYGEPSASQA
  AELRSCYLSSLDLLLEHRLRSVAFPCISTGVFGYPCEAAAEIVLATLREWLEQHKDKVDR
  LIICVFLEKDEDIYRSRLPHYFPVA
• 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. Plays a role in estrogen signaling. Binds to androgen receptor (AR) and amplifies the transactivation function of AR in response to androgen. May play an important role in carcinogenesis and/or progression of hormone-dependent cancers by feed-forward mechanism that activates ESR1 transactivation. Could be an ESR1 coactivator, providing a positive feedback regulatory loop for ESR1 signal transduction. Could be involved in invasive growth by down-regulating CDH1 in endometrial cancer cells. Enhances ESR1-mediated transcription activity.

Molecular Interaction Atlas (MIA) of This DOT

16 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
leukaemia	DISS7D1V	Definitive	Biomarker	[1]
Leukemia	DISNAKFL	Definitive	Biomarker	[1]
Metabolic disorder	DIS71G5H	Definitive	Biomarker	[2]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[3]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[4]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[4]
Cardiovascular disease	DIS2IQDX	Strong	Genetic Variation	[5]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[6]
Endometrial cancer	DISW0LMR	Strong	Altered Expression	[7]
Endometrial carcinoma	DISXR5CY	Strong	Altered Expression	[7]
Gout	DISHC0U7	Strong	Genetic Variation	[8]
Monocytic leukemia	DIS8M755	Strong	Genetic Variation	[9]
Pancreatic cancer	DISJC981	moderate	Biomarker	[1]
Bipolar disorder	DISAM7J2	Limited	Genetic Variation	[10]
Hepatocellular carcinoma	DIS0J828	Limited	Biomarker	[11]
Neoplasm	DISZKGEW	Limited	Altered Expression	[1]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Mitoxantrone	DMM39BF	Approved	ADP-ribose glycohydrolase MACROD1 (MACROD1) affects the response to substance of Mitoxantrone.	[23]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of ADP-ribose glycohydrolase MACROD1 (MACROD1).	[12]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of ADP-ribose glycohydrolase MACROD1 (MACROD1).	[13]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of ADP-ribose glycohydrolase MACROD1 (MACROD1).	[14]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of ADP-ribose glycohydrolase MACROD1 (MACROD1).	[15]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of ADP-ribose glycohydrolase MACROD1 (MACROD1).	[16]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of ADP-ribose glycohydrolase MACROD1 (MACROD1).	[17]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of ADP-ribose glycohydrolase MACROD1 (MACROD1).	[18]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of ADP-ribose glycohydrolase MACROD1 (MACROD1).	[12]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of ADP-ribose glycohydrolase MACROD1 (MACROD1).	[19]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of ADP-ribose glycohydrolase MACROD1 (MACROD1).	[21]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of ADP-ribose glycohydrolase MACROD1 (MACROD1).	[20]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of ADP-ribose glycohydrolase MACROD1 (MACROD1).	[22]

References

• [1] Leukemia-related protein 16 (LRP16) promotes tumor growth and metastasis in pancreatic cancer.Onco Targets Ther. 2018 Mar 5;11:1215-1222. doi: 10.2147/OTT.S157914. eCollection 2018.
• [2] A W-test collapsing method for rare-variant association testing in exome sequencing data.Genet Epidemiol. 2016 Nov;40(7):591-596. doi: 10.1002/gepi.22000. Epub 2016 Aug 16.
• [3] MacroD1 Is a Promiscuous ADP-Ribosyl Hydrolase Localized to Mitochondria.Front Microbiol. 2018 Jan 23;9:20. doi: 10.3389/fmicb.2018.00020. eCollection 2018.
• [4] Correlation between expression of LRP16, Ki67 and EGFR and breast cancer clinical pathologic factors and prognosis.Eur Rev Med Pharmacol Sci. 2017 Jul;21(3 Suppl):47-51.
• [5] Leveraging Polygenic Functional Enrichment to Improve GWAS Power.Am J Hum Genet. 2019 Jan 3;104(1):65-75. doi: 10.1016/j.ajhg.2018.11.008. Epub 2018 Dec 27.
• [6] Blockade of the LRP16-PKR-NF-B signaling axis sensitizes colorectal carcinoma cells to DNA-damaging cytotoxic therapy.Elife. 2017 Aug 18;6:e27301. doi: 10.7554/eLife.27301.
• [7] Induction of the LRP16 gene by estrogen promotes the invasive growth of Ishikawa human endometrial cancer cells through the downregulation of E-cadherin.Cell Res. 2007 Oct;17(10):869-80. doi: 10.1038/cr.2007.79.
• [8] Genome-wide association analyses identify 18 new loci associated with serum urate concentrations. Nat Genet. 2013 Feb;45(2):145-54. doi: 10.1038/ng.2500. Epub 2012 Dec 23.
• [9] LRP16 is fused to RUNX1 in monocytic leukemia cell line with t(11;21)(q13;q22).Eur J Haematol. 2007 Jul;79(1):25-31. doi: 10.1111/j.1600-0609.2007.00858.x. Epub 2007 May 28.
• [10] Genome-wide association study identifies 30 loci associated with bipolar disorder.Nat Genet. 2019 May;51(5):793-803. doi: 10.1038/s41588-019-0397-8. Epub 2019 May 1.
• [11] LRP16 prevents hepatocellular carcinoma progression through regulation of Wnt/-catenin signaling.J Mol Med (Berl). 2018 Jun;96(6):547-558. doi: 10.1007/s00109-018-1639-4. Epub 2018 May 11.
• [12] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [13] Cyclosporine A--induced oxidative stress in human renal mesangial cells: a role for ERK 1/2 MAPK signaling. Toxicol Sci. 2012 Mar;126(1):101-13.
• [14] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [15] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [16] 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.
• [17] 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.
• [18] 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.
• [19] 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.
• [20] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [21] 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.
• [22] 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.
• [23] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.