Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT2HTIAN)

• DOT Name: Dolichol kinase (DOLK)
• Synonyms: EC 2.7.1.108; Transmembrane protein 15
• Gene Name: DOLK
• Related Disease:
  DK1-congenital disorder of glycosylation
  SRD5A3-congenital disorder of glycosylation
  Congenital disorder of glycosylation
  Dilated cardiomyopathy 1A
  Familial dilated cardiomyopathy
  Dilated cardiomyopathy
  Obsolete familial isolated dilated cardiomyopathy
• UniProt ID: DOLK_HUMAN
• EC Number: 2.7.1.108
• Sequence:
  MTRECPSPAPGPGAPLSGSVLAEAAVVFAVVLSIHATVWDRYSWCAVALAVQAFYVQYKW
  DRLLQQGSAVFQFRMSANSGLLPASMVMPLLGLVMKERCQTAGNPFFERFGIVVAATGMA
  VALFSSVLALGITRPVPTNTCVILGLAGGVIIYIMKHSLSVGEVIEVLEVLLIFVYLNMI
  LLYLLPRCFTPGEALLVLGGISFVLNQLIKRSLTLVESQGDPVDFFLLVVVVGMVLMGIF
  FSTLFVFMDSGTWASSIFFHLMTCVLSLGVVLPWLHRLIRRNPLLWLLQFLFQTDTRIYL
  LAYWSLLATLACLVVLYQNAKRSSSESKKHQAPTIARKYFHLIVVATYIPGIIFDRPLLY
  VAATVCLAVFIFLEYVRYFRIKPLGHTLRSFLSLFLDERDSGPLILTHIYLLLGMSLPIW
  LIPRPCTQKGSLGGARALVPYAGVLAVGVGDTVASIFGSTMGEIRWPGTKKTFEGTMTSI
  FAQIISVALILIFDSGVDLNYSYAWILGSISTVSLLEAYTTQIDNLLLPLYLLILLMA
• Function: Catalyzes CTP-mediated phosphorylation of dolichol, the terminal step in de novo dolichyl monophosphate (Dol-P) biosynthesis. Dol-P is a lipid carrier essential for the synthesis of N-linked and O-linked oligosaccharides and for GPI anchors.
• Tissue Specificity: Ubiquitous.
• KEGG Pathway:
  N-Glycan biosynthesis (hsa00510)
  Metabolic pathways (hsa01100)
• Reactome Pathway:
  Defective DOLK causes DOLK-CDG (R-HSA-4755583)
  Synthesis of Dolichyl-phosphate (R-HSA-446199)

Molecular Interaction Atlas (MIA) of This DOT

7 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
DK1-congenital disorder of glycosylation	DISQWUBA	Definitive	Autosomal recessive	[1]
SRD5A3-congenital disorder of glycosylation	DISGHPPC	Definitive	Autosomal recessive	[2]
Congenital disorder of glycosylation	DIS400QP	Strong	Biomarker	[3]
Dilated cardiomyopathy 1A	DIS0RK9Z	Strong	Genetic Variation	[4]
Familial dilated cardiomyopathy	DISBHDU9	Strong	GermlineCausalMutation	[4]
Dilated cardiomyopathy	DISX608J	moderate	Biomarker	[5]
Obsolete familial isolated dilated cardiomyopathy	DIS4FXO4	Supportive	Autosomal dominant	[4]

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 Dolichol kinase (DOLK).	[6]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Dolichol kinase (DOLK).	[7]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Dolichol kinase (DOLK).	[8]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Dolichol kinase (DOLK).	[9]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Dolichol kinase (DOLK).	[10]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Dolichol kinase (DOLK).	[11]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Dolichol kinase (DOLK).	[12]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Dolichol kinase (DOLK).	[13]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Dolichol kinase (DOLK).	[14]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Dolichol kinase (DOLK).	[15]

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] A defect in dolichol phosphate biosynthesis causes a new inherited disorder with death in early infancy. Am J Hum Genet. 2007 Mar;80(3):433-40.
• [3] CDG Therapies: From Bench to Bedside.Int J Mol Sci. 2018 Apr 27;19(5):1304. doi: 10.3390/ijms19051304.
• [4] Autosomal recessive dilated cardiomyopathy due to DOLK mutations results from abnormal dystroglycan O-mannosylation. PLoS Genet. 2011 Dec;7(12):e1002427. doi: 10.1371/journal.pgen.1002427. Epub 2011 Dec 29.
• [5] Severe, fatal multisystem manifestations in a patient with dolichol kinase-congenital disorder of glycosylation.Mol Genet Metab. 2013 Dec;110(4):484-9. doi: 10.1016/j.ymgme.2013.09.016. Epub 2013 Oct 4.
• [6] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [7] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [8] 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.
• [9] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [10] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [11] 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.
• [12] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [13] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [14] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [15] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.