Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTPSW8Y8)

• DOT Name: Macrophage immunometabolism regulator (MACIR)
• Gene Name: MACIR
• Related Disease:
  Coronary heart disease
  Hepatocellular carcinoma
  Hypothyroidism
  Multiple sclerosis
  Prostate cancer
  Prostate carcinoma
  Autoimmune disease
  Immune system disorder
  Arthritis
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Colon cancer
  Colonic neoplasm
  Esophageal cancer
  Glioblastoma multiforme
  Liver cancer
  Neoplasm of esophagus
  Non-small-cell lung cancer
  Ovarian cancer
  Ovarian neoplasm
  Prostate neoplasm
  Rheumatoid arthritis
• UniProt ID: MACIR_HUMAN
• Pfam ID: PF15435
• Sequence:
  MEVDINGESRSTLTTLPFPGAEANSPGKAEAEKPRCSSTPCSPMRRTVSGYQILHMDSNY
  LVGFTTGEELLKLAQKCTGGEESKAEAMPSLRSKQLDAGLARSSRLYKTRSRYYQPYEIP
  AVNGRRRRRMPSSGDKCTKSLPYEPYKALHGPLPLCLLKGKRAHSKSLDYLNLDKMIKEP
  ADTEVLQYQLQHLTLRGDRVFARNNT
• Function: Regulates the macrophage function, by enhancing the resolution of inflammation and wound repair functions mediated by M2 macrophages. The regulation of macrophage function is, due at least in part, to its ability to inhibit glycolysis. May also play a role in trafficking of proteins via its interaction with UNC119 and UNC119B cargo adapters: may help the release of UNC119 and UNC119B cargo or the recycling of UNC119 and UNC119B. May play a role in ciliary membrane localization via its interaction with UNC119B and protein transport into photoreceptor cells.
• Tissue Specificity: High expression in normal macrophages, monocytes, and cultured rheumatoid arthritis synovial fibroblasts (RASFs), with lower expression in B- and T-cells, and little to no expression in other tissues and cell lines.

Molecular Interaction Atlas (MIA) of This DOT

23 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Coronary heart disease	DIS5OIP1	Definitive	Genetic Variation	[1]
Hepatocellular carcinoma	DIS0J828	Definitive	Biomarker	[2]
Hypothyroidism	DISR0H6D	Strong	Genetic Variation	[3]
Multiple sclerosis	DISB2WZI	Strong	Genetic Variation	[4]
Prostate cancer	DISF190Y	Strong	Biomarker	[5]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[6]
Autoimmune disease	DISORMTM	moderate	Genetic Variation	[7]
Immune system disorder	DISAEGPH	moderate	Genetic Variation	[7]
Arthritis	DIST1YEL	Limited	Altered Expression	[8]
Breast cancer	DIS7DPX1	Limited	Biomarker	[5]
Breast carcinoma	DIS2UE88	Limited	Biomarker	[5]
Breast neoplasm	DISNGJLM	Limited	Biomarker	[5]
Colon cancer	DISVC52G	Limited	Biomarker	[5]
Colonic neoplasm	DISSZ04P	Limited	Biomarker	[5]
Esophageal cancer	DISGB2VN	Limited	Biomarker	[5]
Glioblastoma multiforme	DISK8246	Limited	Biomarker	[5]
Liver cancer	DISDE4BI	Limited	Biomarker	[5]
Neoplasm of esophagus	DISOLKAQ	Limited	Biomarker	[5]
Non-small-cell lung cancer	DIS5Y6R9	Limited	Biomarker	[5]
Ovarian cancer	DISZJHAP	Limited	Biomarker	[5]
Ovarian neoplasm	DISEAFTY	Limited	Biomarker	[5]
Prostate neoplasm	DISHDKGQ	Limited	Biomarker	[5]
Rheumatoid arthritis	DISTSB4J	Limited	Genetic Variation	[9]

10 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 Macrophage immunometabolism regulator (MACIR).	[10]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Macrophage immunometabolism regulator (MACIR).	[11]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Macrophage immunometabolism regulator (MACIR).	[12]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Macrophage immunometabolism regulator (MACIR).	[14]
Selenium	DM25CGV	Approved	Selenium decreases the expression of Macrophage immunometabolism regulator (MACIR).	[15]
Demecolcine	DMCZQGK	Approved	Demecolcine decreases the expression of Macrophage immunometabolism regulator (MACIR).	[16]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene decreases the expression of Macrophage immunometabolism regulator (MACIR).	[12]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Macrophage immunometabolism regulator (MACIR).	[18]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Macrophage immunometabolism regulator (MACIR).	[20]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Macrophage immunometabolism regulator (MACIR).	[21]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Macrophage immunometabolism regulator (MACIR).	[13]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Macrophage immunometabolism regulator (MACIR).	[17]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Macrophage immunometabolism regulator (MACIR).	[19]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Macrophage immunometabolism regulator (MACIR).	[22]

References

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• [2] Detection of fusion transcripts in the serum samples of patients with hepatocellular carcinoma.Oncotarget. 2019 May 21;10(36):3352-3360. eCollection 2019 May 21.
• [3] 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.
• [4] Genome-wide meta-analysis identifies novel multiple sclerosis susceptibility loci.Ann Neurol. 2011 Dec;70(6):897-912. doi: 10.1002/ana.22609.
• [5] Identification of recurrent fusion genes across multiple cancer types.Sci Rep. 2019 Jan 31;9(1):1074. doi: 10.1038/s41598-019-38550-6.
• [6] Novel fusion transcripts associate with progressive prostate cancer.Am J Pathol. 2014 Oct;184(10):2840-9. doi: 10.1016/j.ajpath.2014.06.025.
• [7] Meta-analysis of genome-wide association studies in celiac disease and rheumatoid arthritis identifies fourteen non-HLA shared loci.PLoS Genet. 2011 Feb;7(2):e1002004. doi: 10.1371/journal.pgen.1002004. Epub 2011 Feb 24.
• [8] The Autoimmune Susceptibility Gene C5orf30 Regulates Macrophage-Mediated Resolution of Inflammation.J Immunol. 2019 Feb 15;202(4):1069-1078. doi: 10.4049/jimmunol.1801155. Epub 2019 Jan 18.
• [9] Genetic influences on susceptibility to rheumatoid arthritis in African-Americans.Hum Mol Genet. 2019 Mar 1;28(5):858-874. doi: 10.1093/hmg/ddy395.
• [10] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [11] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [12] Differential modulation of PI3-kinase/Akt pathway during all-trans retinoic acid- and Am80-induced HL-60 cell differentiation revealed by DNA microarray analysis. Biochem Pharmacol. 2004 Dec 1;68(11):2177-86.
• [13] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [14] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [15] 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.
• [16] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [17] 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.
• [18] 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.
• [19] 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.
• [20] 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.
• [21] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.
• [22] 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.