Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTUU22PK)

• DOT Name: Alpha-methylacyl-CoA racemase (AMACR)
• Synonyms: EC 5.1.99.4; 2-methylacyl-CoA racemase
• Gene Name: AMACR
• Related Disease:
  Alpha-methylacyl-CoA racemase deficiency
  Congenital bile acid synthesis defect 4
• UniProt ID: AMACR_HUMAN
• EC Number: 5.1.99.4
• Pfam ID: PF02515
• Sequence:
  MALQGISVVELSGLAPGPFCAMVLADFGARVVRVDRPGSRYDVSRLGRGKRSLVLDLKQP
  RGAAVLRRLCKRSDVLLEPFRRGVMEKLQLGPEILQRENPRLIYARLSGFGQSGSFCRLA
  GHDINYLALSGVLSKIGRSGENPYAPLNLLADFAGGGLMCALGIIMALFDRTRTGKGQVI
  DANMVEGTAYLSSFLWKTQKLSLWEAPRGQNMLDGGAPFYTTYRTADGEFMAVGAIEPQF
  YELLIKGLGLKSDELPNQMSMDDWPEMKKKFADVFAEKTKAEWCQIFDGTDACVTPVLTF
  EEVVHHDHNKERGSFITSEEQDVSPRPAPLLLNTPAIPSFKRDPFIGEHTEEILEEFGFS
  REEIYQLNSDKIIESNKVKASL
• Function: Catalyzes the interconversion of (R)- and (S)-stereoisomers of alpha-methyl-branched-chain fatty acyl-CoA esters. Acts only on coenzyme A thioesters, not on free fatty acids, and accepts as substrates a wide range of alpha-methylacyl-CoAs, including pristanoyl-CoA, trihydroxycoprostanoyl-CoA (an intermediate in bile acid synthesis), and arylpropionic acids like the anti-inflammatory drug ibuprofen (2-(4-isobutylphenyl)propionic acid) but neither 3-methyl-branched nor linear-chain acyl-CoAs.
• KEGG Pathway:
  Primary bile acid biosynthesis (hsa00120)
  Metabolic pathways (hsa01100)
  Peroxisome (hsa04146)
• Reactome Pathway:
  Synthesis of bile acids and bile salts via 24-hydroxycholesterol (R-HSA-193775)
  Beta-oxidation of pristanoyl-CoA (R-HSA-389887)
  Peroxisomal protein import (R-HSA-9033241)
  Synthesis of bile acids and bile salts via 7alpha-hydroxycholesterol (R-HSA-193368)
• BioCyc Pathway: MetaCyc:HS01416-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Alpha-methylacyl-CoA racemase deficiency	DISMSQ7I	Definitive	Autosomal recessive	[1]
Congenital bile acid synthesis defect 4	DISYYKA6	Supportive	Autosomal recessive	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Alpha-methylacyl-CoA racemase (AMACR).	[3]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Alpha-methylacyl-CoA racemase (AMACR).	[4]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Alpha-methylacyl-CoA racemase (AMACR).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Alpha-methylacyl-CoA racemase (AMACR).	[6]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Alpha-methylacyl-CoA racemase (AMACR).	[7]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Alpha-methylacyl-CoA racemase (AMACR).	[4]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Alpha-methylacyl-CoA racemase (AMACR).	[8]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Alpha-methylacyl-CoA racemase (AMACR).	[9]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Alpha-methylacyl-CoA racemase (AMACR).	[10]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Alpha-methylacyl-CoA racemase (AMACR).	[11]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Alpha-methylacyl-CoA racemase (AMACR).	[12]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of Alpha-methylacyl-CoA racemase (AMACR).	[13]
Amphotericin B	DMTAJQE	Approved	Amphotericin B decreases the expression of Alpha-methylacyl-CoA racemase (AMACR).	[14]
Bicalutamide	DMZMSPF	Approved	Bicalutamide decreases the expression of Alpha-methylacyl-CoA racemase (AMACR).	[15]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Alpha-methylacyl-CoA racemase (AMACR).	[16]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Alpha-methylacyl-CoA racemase (AMACR).	[17]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Alpha-methylacyl-CoA racemase (AMACR).	[18]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Alpha-methylacyl-CoA racemase (AMACR).	[19]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Alpha-methylacyl-CoA racemase (AMACR).	[20]
(E)-4-(3,5-dimethoxystyryl)phenol	DMYXI2V	Investigative	(E)-4-(3,5-dimethoxystyryl)phenol decreases the expression of Alpha-methylacyl-CoA racemase (AMACR).	[21]

References

• [1] Mutations in the gene encoding peroxisomal alpha-methylacyl-CoA racemase cause adult-onset sensory motor neuropathy. Nat Genet. 2000 Feb;24(2):188-91. doi: 10.1038/72861.
• [2] Mechanisms of disease: Inborn errors of bile acid synthesis. Nat Clin Pract Gastroenterol Hepatol. 2008 Aug;5(8):456-68. doi: 10.1038/ncpgasthep1179. Epub 2008 Jun 24.
• [3] Integrated 'omics analysis reveals new drug-induced mitochondrial perturbations in human hepatocytes. Toxicol Lett. 2018 Jun 1;289:1-13.
• [4] 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.
• [5] 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.
• [6] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [7] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [8] Multifaceted preventive effects of single agent quercetin on a human prostate adenocarcinoma cell line (PC-3): implications for nutritional transcriptomics and multi-target therapy. Med Oncol. 2011 Dec;28(4):1395-404. doi: 10.1007/s12032-010-9603-3. Epub 2010 Jul 2.
• [9] Identification of transcriptome signatures and biomarkers specific for potential developmental toxicants inhibiting human neural crest cell migration. Arch Toxicol. 2016 Jan;90(1):159-80.
• [10] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [11] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [12] The contribution of methotrexate exposure and host factors on transcriptional variance in human liver. Toxicol Sci. 2007 Jun;97(2):582-94.
• [13] Temporal changes in gene expression in the skin of patients treated with isotretinoin provide insight into its mechanism of action. Dermatoendocrinol. 2009 May;1(3):177-87.
• [14] Differential expression of microRNAs and their predicted targets in renal cells exposed to amphotericin B and its complex with copper (II) ions. Toxicol Mech Methods. 2017 Sep;27(7):537-543. doi: 10.1080/15376516.2017.1333554. Epub 2017 Jun 8.
• [15] Microarray analysis of bicalutamide action on telomerase activity, p53 pathway and viability of prostate carcinoma cell lines. J Pharm Pharmacol. 2005 Jan;57(1):83-92.
• [16] LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
• [17] 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.
• [18] Synergistic effect of JQ1 and rapamycin for treatment of human osteosarcoma. Int J Cancer. 2015 May 1;136(9):2055-64.
• [19] Characterization of the Molecular Alterations Induced by the Prolonged Exposure of Normal Colon Mucosa and Colon Cancer Cells to Low-Dose Bisphenol A. Int J Mol Sci. 2022 Oct 1;23(19):11620. doi: 10.3390/ijms231911620.
• [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] In vitro evaluation of the cytotoxic, anti-proliferative and anti-oxidant properties of pterostilbene isolated from Pterocarpus marsupium. Toxicol In Vitro. 2010 Jun;24(4):1215-28. doi: 10.1016/j.tiv.2010.02.007. Epub 2010 Feb 10.