Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT3FL9W0)

• DOT Name: ATP-binding cassette sub-family D member 1 (ABCD1)
• Synonyms: EC 3.1.2.-; EC 7.6.2.-; Adrenoleukodystrophy protein; ALDP
• Gene Name: ABCD1
• Related Disease:
  Adrenoleukodystrophy
  X-linked cerebral adrenoleukodystrophy
  Hereditary spastic paraplegia
  Adrenomyeloneuropathy
  Hirschsprung disease
• UniProt ID: ABCD1_HUMAN
• PDB ID: 7RR9; 7RRA; 7SHM; 7SHN; 7VR1; 7VWC; 7VX8; 7VZB; 7X07; 7X0T; 7X0Z; 7X1W; 7XEC; 7YRQ
• EC Number: 3.1.2.-; 7.6.2.-
• Pfam ID: PF06472 ; PF00005
• Sequence:
  MPVLSRPRPWRGNTLKRTAVLLALAAYGAHKVYPLVRQCLAPARGLQAPAGEPTQEASGV
  AAAKAGMNRVFLQRLLWLLRLLFPRVLCRETGLLALHSAALVSRTFLSVYVARLDGRLAR
  CIVRKDPRAFGWQLLQWLLIALPATFVNSAIRYLEGQLALSFRSRLVAHAYRLYFSQQTY
  YRVSNMDGRLRNPDQSLTEDVVAFAASVAHLYSNLTKPLLDVAVTSYTLLRAARSRGAGT
  AWPSAIAGLVVFLTANVLRAFSPKFGELVAEEARRKGELRYMHSRVVANSEEIAFYGGHE
  VELALLQRSYQDLASQINLILLERLWYVMLEQFLMKYVWSASGLLMVAVPIITATGYSES
  DAEAVKKAALEKKEEELVSERTEAFTIARNLLTAAADAIERIMSSYKEVTELAGYTARVH
  EMFQVFEDVQRCHFKRPRELEDAQAGSGTIGRSGVRVEGPLKIRGQVVDVEQGIICENIP
  IVTPSGEVVVASLNIRVEEGMHLLITGPNGCGKSSLFRILGGLWPTYGGVLYKPPPQRMF
  YIPQRPYMSVGSLRDQVIYPDSVEDMQRKGYSEQDLEAILDVVHLHHILQREGGWEAMCD
  WKDVLSGGEKQRIGMARMFYHRPKYALLDECTSAVSIDVEGKIFQAAKDAGIALLSITHR
  PSLWKYHTHLLQFDGEGGWKFEKLDSAARLSLTEEKQRLEQQLAGIPKMQRRLQELCQIL
  GEAVAPAHVPAPSPQGPGGLQGAST
• Function: ATP-dependent transporter of the ATP-binding cassette (ABC) family involved in the transport of very long chain fatty acid (VLCFA)-CoA from the cytosol to the peroxisome lumen. Coupled to the ATP-dependent transporter activity has also a fatty acyl-CoA thioesterase activity (ACOT) and hydrolyzes VLCFA-CoA into VLCFA prior their ATP-dependent transport into peroxisomes, the ACOT activity is essential during this transport process. Thus, plays a role in regulation of VLCFAs and energy metabolism namely, in the degradation and biosynthesis of fatty acids by beta-oxidation, mitochondrial function and microsomal fatty acid elongation. Involved in several processes; namely, controls the active myelination phase by negatively regulating the microsomal fatty acid elongation activity and may also play a role in axon and myelin maintenance. Controls also the cellular response to oxidative stress by regulating mitochondrial functions such as mitochondrial oxidative phosphorylation and depolarization. And finally controls the inflammatory response by positively regulating peroxisomal beta-oxidation of VLCFAs.
• KEGG Pathway:
  ABC transporters (hsa02010)
  Peroxisome (hsa04146)
• Reactome Pathway:
  Linoleic acid (LA) metabolism (R-HSA-2046105)
  alpha-linolenic acid (ALA) metabolism (R-HSA-2046106)
  Beta-oxidation of very long chain fatty acids (R-HSA-390247)
  Defective ABCD1 causes ALD (R-HSA-5684045)
  Class I peroxisomal membrane protein import (R-HSA-9603798)
  ABC transporters in lipid homeostasis (R-HSA-1369062)

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adrenoleukodystrophy	DISTUD1F	Definitive	X-linked	[1]
X-linked cerebral adrenoleukodystrophy	DISLN6PA	Definitive	X-linked	[2]
Hereditary spastic paraplegia	DISGZQV1	Strong	X-linked	[2]
Adrenomyeloneuropathy	DISPTS3P	Supportive	X-linked	[3]
Hirschsprung disease	DISUUSM1	Supportive	Autosomal dominant	[4]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of ATP-binding cassette sub-family D member 1 (ABCD1).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of ATP-binding cassette sub-family D member 1 (ABCD1).	[6]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of ATP-binding cassette sub-family D member 1 (ABCD1).	[7]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of ATP-binding cassette sub-family D member 1 (ABCD1).	[8]
Zidovudine	DM4KI7O	Approved	Zidovudine increases the expression of ATP-binding cassette sub-family D member 1 (ABCD1).	[9]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of ATP-binding cassette sub-family D member 1 (ABCD1).	[10]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of ATP-binding cassette sub-family D member 1 (ABCD1).	[11]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of ATP-binding cassette sub-family D member 1 (ABCD1).	[12]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of ATP-binding cassette sub-family D member 1 (ABCD1).	[13]

References

• [1] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [2] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [3] X-Linked Adrenoleukodystrophy. 1999 Mar 26 [updated 2023 Apr 6]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews(?) [Internet]. Seattle (WA): University of Washington, Seattle; 1993C2024.
• [4] A complementary study approach unravels novel players in the pathoetiology of Hirschsprung disease. PLoS Genet. 2020 Nov 5;16(11):e1009106. doi: 10.1371/journal.pgen.1009106. eCollection 2020 Nov.
• [5] 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.
• [6] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [7] 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.
• [8] The contribution of methotrexate exposure and host factors on transcriptional variance in human liver. Toxicol Sci. 2007 Jun;97(2):582-94.
• [9] Differential gene expression in human hepatocyte cell lines exposed to the antiretroviral agent zidovudine. Arch Toxicol. 2014 Mar;88(3):609-23. doi: 10.1007/s00204-013-1169-3. Epub 2013 Nov 30.
• [10] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [11] 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.
• [12] 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.
• [13] Alternatives for the worse: Molecular insights into adverse effects of bisphenol a and substitutes during human adipocyte differentiation. Environ Int. 2021 Nov;156:106730. doi: 10.1016/j.envint.2021.106730. Epub 2021 Jun 27.