Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTF6LWPO)

• DOT Name: Dihydroxyacetone phosphate acyltransferase (GNPAT)
• Synonyms: DAP-AT; DAPAT; DHAP-AT; EC 2.3.1.42; Acyl-CoA:dihydroxyacetonephosphateacyltransferase; Glycerone-phosphate O-acyltransferase
• Gene Name: GNPAT
• Related Disease:
  Glyceronephosphate O-acyltransferase deficiency
  Rhizomelic chondrodysplasia punctata type 2
  Alzheimer disease
  Attention deficit hyperactivity disorder
  Chondrodysplasia punctata
  Rhizomelic chondrodysplasia punctata
  Schizophrenia
  X-linked chondrodysplasia punctata 2
  Advanced cancer
  Autism
  Carcinoma of liver and intrahepatic biliary tract
  Hepatocellular carcinoma
  Liver cancer
  Neurodevelopmental disorder
  Zellweger spectrum disorders
• UniProt ID: GNPAT_HUMAN
• EC Number: 2.3.1.42
• Pfam ID: PF01553 ; PF19277
• Sequence:
  MESSSSSNSYFSVGPTSPSAVVLLYSKELKKWDEFEDILEERRHVSDLKFAMKCYTPLVY
  KGITPCKPIDIKCSVLNSEEIHYVIKQLSKESLQSVDVLREEVSEILDEMSHKLRLGAIR
  FCAFTLSKVFKQIFSKVCVNEEGIQKLQRAIQEHPVVLLPSHRSYIDFLMLSFLLYNYDL
  PVPVIAAGMDFLGMKMVGELLRMSGAFFMRRTFGGNKLYWAVFSEYVKTMLRNGYAPVEF
  FLEGTRSRSAKTLTPKFGLLNIVMEPFFKREVFDTYLVPISISYDKILEETLYVYELLGV
  PKPKESTTGLLKARKILSENFGSIHVYFGDPVSLRSLAAGRMSRSSYNLVPRYIPQKQSE
  DMHAFVTEVAYKMELLQIENMVLSPWTLIVAVLLQNRPSMDFDALVEKTLWLKGLTQAFG
  GFLIWPDNKPAEEVVPASILLHSNIASLVKDQVILKVDSGDSEVVDGLMLQHITLLMCSA
  YRNQLLNIFVRPSLVAVALQMTPGFRKEDVYSCFRFLRDVFADEFIFLPGNTLKDFEEGC
  YLLCKSEAIQVTTKDILVTEKGNTVLEFLVGLFKPFVESYQIICKYLLSEEEDHFSEEQY
  LAAVRKFTSQLLDQGTSQCYDVLSSDVQKNALAACVRLGVVEKKKINNNCIFNVNEPATT
  KLEEMLGCKTPIGKPATAKL
• Function: Dihydroxyacetonephosphate acyltransferase catalyzing the first step in the biosynthesis of plasmalogens, a subset of phospholipids that differ from other glycerolipids by having an alkyl chain attached through a vinyl ether linkage at the sn-1 position of the glycerol backbone, and which unique physical properties have an impact on various aspects of cell signaling and membrane biology.
• KEGG Pathway:
  Glycerophospholipid metabolism (hsa00564)
  Peroxisome (hsa04146)
• Reactome Pathway:
  Plasmalogen biosynthesis (R-HSA-75896)
  Peroxisomal protein import (R-HSA-9033241)
  Synthesis of PA (R-HSA-1483166)
• BioCyc Pathway: MetaCyc:HS04068-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

15 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Glyceronephosphate O-acyltransferase deficiency	DISN8INP	Definitive	Autosomal recessive	[1]
Rhizomelic chondrodysplasia punctata type 2	DISD2C41	Definitive	Autosomal recessive	[2]
Alzheimer disease	DISF8S70	Strong	Altered Expression	[3]
Attention deficit hyperactivity disorder	DISL8MX9	Strong	Biomarker	[4]
Chondrodysplasia punctata	DISERVGO	Strong	Biomarker	[5]
Rhizomelic chondrodysplasia punctata	DISF3YE7	Strong	Genetic Variation	[6]
Schizophrenia	DISSRV2N	Strong	Biomarker	[7]
X-linked chondrodysplasia punctata 2	DISI20G2	Strong	Biomarker	[8]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[9]
Autism	DISV4V1Z	Limited	Biomarker	[4]
Carcinoma of liver and intrahepatic biliary tract	DIS8WA0W	Limited	Biomarker	[9]
Hepatocellular carcinoma	DIS0J828	Limited	Biomarker	[9]
Liver cancer	DISDE4BI	Limited	Biomarker	[9]
Neurodevelopmental disorder	DIS372XH	Limited	Biomarker	[4]
Zellweger spectrum disorders	DISW52CE	Limited	Biomarker	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Dihydroxyacetone phosphate acyltransferase (GNPAT).	[11]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Dihydroxyacetone phosphate acyltransferase (GNPAT).	[12]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Dihydroxyacetone phosphate acyltransferase (GNPAT).	[13]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Dihydroxyacetone phosphate acyltransferase (GNPAT).	[14]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Dihydroxyacetone phosphate acyltransferase (GNPAT).	[15]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Dihydroxyacetone phosphate acyltransferase (GNPAT).	[16]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of Dihydroxyacetone phosphate acyltransferase (GNPAT).	[17]
Hydrocortisone	DMGEMB7	Approved	Hydrocortisone increases the expression of Dihydroxyacetone phosphate acyltransferase (GNPAT).	[18]
Lithium chloride	DMHYLQ2	Investigative	Lithium chloride decreases the expression of Dihydroxyacetone phosphate acyltransferase (GNPAT).	[21]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Dihydroxyacetone phosphate acyltransferase (GNPAT).	[19]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Dihydroxyacetone phosphate acyltransferase (GNPAT).	[20]

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] Developmental delay and growth failure caused by a peroxisomal disorder, dihydroxyacetonephosphate acyltransferase (DHAP-AT) deficiency. Am J Med Genet. 1998 Nov 16;80(3):223-6.
• [3] Reduction of Ether-Type Glycerophospholipids, Plasmalogens, by NF-B Signal Leading to Microglial Activation.J Neurosci. 2017 Apr 12;37(15):4074-4092. doi: 10.1523/JNEUROSCI.3941-15.2017. Epub 2017 Mar 14.
• [4] Disturbed neurotransmitter homeostasis in ether lipid deficiency.Hum Mol Genet. 2019 Jun 15;28(12):2046-2061. doi: 10.1093/hmg/ddz040.
• [5] Defects in myelination, paranode organization and Purkinje cell innervation in the ether lipid-deficient mouse cerebellum.Hum Mol Genet. 2009 Jun 1;18(11):1897-908. doi: 10.1093/hmg/ddp110. Epub 2009 Mar 8.
• [6] A peroxisomal disorder of severe intellectual disability, epilepsy, and cataracts due to fatty acyl-CoA reductase 1 deficiency. Am J Hum Genet. 2014 Nov 6;95(5):602-10. doi: 10.1016/j.ajhg.2014.10.003. Epub 2014 Oct 30.
• [7] A single nucleotide polymorphism fine mapping study of chromosome 1q42.1 reveals the vulnerability genes for schizophrenia, GNPAT and DISC1: Association with impairment of sustained attention.Biol Psychiatry. 2006 Sep 15;60(6):554-62. doi: 10.1016/j.biopsych.2006.04.024.
• [8] X-linked dominant chondrodysplasia punctata with decreased dihydroxyacetone phosphate acyltransferase activity.Dermatology. 1996;192(1):23-7. doi: 10.1159/000246308.
• [9] Amplification of Glyceronephosphate O-Acyltransferase and Recruitment of USP30 Stabilize DRP1 to Promote Hepatocarcinogenesis.Cancer Res. 2018 Oct 15;78(20):5808-5819. doi: 10.1158/0008-5472.CAN-18-0340. Epub 2018 Aug 24.
• [10] Neonatal punctate calcifications associated with maternal mixed connective tissue disorder (MCTD).BMJ Case Rep. 2018 Oct 12;2018:bcr2017223373. doi: 10.1136/bcr-2017-223373.
• [11] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [12] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [13] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [14] 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.
• [15] 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.
• [16] 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.
• [17] 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.
• [18] Hydrocortisone enhances the barrier properties of HBMEC/ci, a brain microvascular endothelial cell line, through mesenchymal-to-endothelial transition-like effects. Fluids Barriers CNS. 2015 Mar 5;12:7. doi: 10.1186/s12987-015-0003-0. eCollection 2015.
• [19] 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.
• [20] 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.
• [21] Effects of lithium and valproic acid on gene expression and phenotypic markers in an NT2 neurosphere model of neural development. PLoS One. 2013;8(3):e58822.