Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTR1XD9B)

• DOT Name: Glycerol-3-phosphate acyltransferase 1, mitochondrial (GPAM)
• Synonyms: GPAT-1; EC 2.3.1.15
• Gene Name: GPAM
• Related Disease:
  Fatty liver disease
  Melanoma
  Nephrotic syndrome
  Overnutrition
  Advanced cancer
  Obesity
• UniProt ID: GPAT1_HUMAN
• PDB ID: 8E4Y; 8E50
• EC Number: 2.3.1.15
• Pfam ID: PF01553 ; PF19277
• Sequence:
  MDESALTLGTIDVSYLPHSSEYSVGRCKHTSEEWGECGFRPTIFRSATLKWKESLMSRKR
  PFVGRCCYSCTPQSWDKFFNPSIPSLGLRNVIYINETHTRHRGWLARRLSYVLFIQERDV
  HKGMFATNVTENVLNSSRVQEAIAEVAAELNPDGSAQQQSKAVNKVKKKAKRILQEMVAT
  VSPAMIRLTGWVLLKLFNSFFWNIQIHKGQLEMVKAATETNLPLLFLPVHRSHIDYLLLT
  FILFCHNIKAPYIASGNNLNIPIFSTLIHKLGGFFIRRRLDETPDGRKDVLYRALLHGHI
  VELLRQQQFLEIFLEGTRSRSGKTSCARAGLLSVVVDTLSTNVIPDILIIPVGISYDRII
  EGHYNGEQLGKPKKNESLWSVARGVIRMLRKNYGCVRVDFAQPFSLKEYLESQSQKPVSA
  LLSLEQALLPAILPSRPSDAADEGRDTSINESRNATDESLRRRLIANLAEHILFTASKSC
  AIMSTHIVACLLLYRHRQGIDLSTLVEDFFVMKEEVLARDFDLGFSGNSEDVVMHAIQLL
  GNCVTITHTSRNDEFFITPSTTVPSVFELNFYSNGVLHVFIMEAIIACSLYAVLNKRGLG
  GPTSTPPNLISQEQLVRKAASLCYLLSNEGTISLPCQTFYQVCHETVGKFIQYGILTVAE
  HDDQEDISPSLAEQQWDKKLPEPLSWRSDEEDEDSDFGEEQRDCYLKVSQSKEHQQFITF
  LQRLLGPLLEAYSSAAIFVHNFSGPVPEPEYLQKLHKYLITRTERNVAVYAESATYCLVK
  NAVKMFKDIGVFKETKQKRVSVLELSSTFLPQCNRQKLLEYILSFVVL
• Function: Esterifies acyl-group from acyl-ACP to the sn-1 position of glycerol-3-phosphate, an essential step in glycerolipids biosynthesis such as triglycerides, phosphatidic acids and lysophosphatidic acids.
• KEGG Pathway:
  Glycerolipid metabolism (hsa00561)
  Glycerophospholipid metabolism (hsa00564)
  Metabolic pathways (hsa01100)
• Reactome Pathway:
  Activation of gene expression by SREBF (SREBP) (R-HSA-2426168)
  Triglyceride biosynthesis (R-HSA-75109)
  RUNX1 regulates estrogen receptor mediated transcription (R-HSA-8931987)
  Estrogen-dependent gene expression (R-HSA-9018519)
  Synthesis of PA (R-HSA-1483166)
• BioCyc Pathway: MetaCyc:57678-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

6 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Fatty liver disease	DIS485QZ	Strong	Altered Expression	[1]
Melanoma	DIS1RRCY	Strong	Biomarker	[2]
Nephrotic syndrome	DISSPSC2	Strong	Biomarker	[3]
Overnutrition	DISGAJIG	Strong	Altered Expression	[1]
Advanced cancer	DISAT1Z9	Limited	Altered Expression	[4]
Obesity	DIS47Y1K	Limited	Biomarker	[5]

25 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 Glycerol-3-phosphate acyltransferase 1, mitochondrial (GPAM).	[6]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Glycerol-3-phosphate acyltransferase 1, mitochondrial (GPAM).	[7]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Glycerol-3-phosphate acyltransferase 1, mitochondrial (GPAM).	[8]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Glycerol-3-phosphate acyltransferase 1, mitochondrial (GPAM).	[9]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate affects the expression of Glycerol-3-phosphate acyltransferase 1, mitochondrial (GPAM).	[10]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Glycerol-3-phosphate acyltransferase 1, mitochondrial (GPAM).	[7]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Glycerol-3-phosphate acyltransferase 1, mitochondrial (GPAM).	[11]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Glycerol-3-phosphate acyltransferase 1, mitochondrial (GPAM).	[12]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Glycerol-3-phosphate acyltransferase 1, mitochondrial (GPAM).	[13]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Glycerol-3-phosphate acyltransferase 1, mitochondrial (GPAM).	[14]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of Glycerol-3-phosphate acyltransferase 1, mitochondrial (GPAM).	[15]
Troglitazone	DM3VFPD	Approved	Troglitazone decreases the expression of Glycerol-3-phosphate acyltransferase 1, mitochondrial (GPAM).	[16]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone increases the expression of Glycerol-3-phosphate acyltransferase 1, mitochondrial (GPAM).	[17]
Ethanol	DMDRQZU	Approved	Ethanol decreases the expression of Glycerol-3-phosphate acyltransferase 1, mitochondrial (GPAM).	[18]
Obeticholic acid	DM3Q1SM	Approved	Obeticholic acid decreases the expression of Glycerol-3-phosphate acyltransferase 1, mitochondrial (GPAM).	[19]
Entacapone	DMLBVKQ	Approved	Entacapone decreases the expression of Glycerol-3-phosphate acyltransferase 1, mitochondrial (GPAM).	[20]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Glycerol-3-phosphate acyltransferase 1, mitochondrial (GPAM).	[21]
OTX-015	DMI8RG1	Phase 1/2	OTX-015 decreases the expression of Glycerol-3-phosphate acyltransferase 1, mitochondrial (GPAM).	[22]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Glycerol-3-phosphate acyltransferase 1, mitochondrial (GPAM).	[23]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Glycerol-3-phosphate acyltransferase 1, mitochondrial (GPAM).	[22]
Mivebresib	DMCPF90	Phase 1	Mivebresib decreases the expression of Glycerol-3-phosphate acyltransferase 1, mitochondrial (GPAM).	[22]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Glycerol-3-phosphate acyltransferase 1, mitochondrial (GPAM).	[24]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Glycerol-3-phosphate acyltransferase 1, mitochondrial (GPAM).	[26]
Hexadecanoic acid	DMWUXDZ	Investigative	Hexadecanoic acid increases the expression of Glycerol-3-phosphate acyltransferase 1, mitochondrial (GPAM).	[27]
Dibutyl phthalate	DMEDGKO	Investigative	Dibutyl phthalate increases the expression of Glycerol-3-phosphate acyltransferase 1, mitochondrial (GPAM).	[28]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Glycerol-3-phosphate acyltransferase 1, mitochondrial (GPAM).	[25]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Glycerol-3-phosphate acyltransferase 1, mitochondrial (GPAM).	[25]

References

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• [4] Glycerol-3-phosphate Acyltransferase 1 Promotes Tumor Cell Migration and Poor Survival in Ovarian Carcinoma.Cancer Res. 2017 Sep 1;77(17):4589-4601. doi: 10.1158/0008-5472.CAN-16-2065. Epub 2017 Jun 26.
• [5] Increased lipogenic capacity of the islets of obese rats: a role in the pathogenesis of NIDDM.Diabetes. 1997 Mar;46(3):408-13. doi: 10.2337/diab.46.3.408.
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• [10] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [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] Minimal peroxide exposure of neuronal cells induces multifaceted adaptive responses. PLoS One. 2010 Dec 17;5(12):e14352. doi: 10.1371/journal.pone.0014352.
• [13] 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.
• [14] The contribution of methotrexate exposure and host factors on transcriptional variance in human liver. Toxicol Sci. 2007 Jun;97(2):582-94.
• [15] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [16] Transcriptomic analysis of untreated and drug-treated differentiated HepaRG cells over a 2-week period. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):27-35.
• [17] Replacement per- and polyfluoroalkyl substances (PFAS) are potent modulators of lipogenic and drug metabolizing gene expression signatures in primary human hepatocytes. Toxicol Appl Pharmacol. 2022 May 1;442:115991. doi: 10.1016/j.taap.2022.115991. Epub 2022 Mar 23.
• [18] Chronic ethanol exposure increases goosecoid (GSC) expression in human embryonic carcinoma cell differentiation. J Appl Toxicol. 2014 Jan;34(1):66-75.
• [19] Pharmacotoxicology of clinically-relevant concentrations of obeticholic acid in an organotypic human hepatocyte system. Toxicol In Vitro. 2017 Mar;39:93-103.
• [20] Effect of the Catechol-O-Methyltransferase Inhibitors Tolcapone and Entacapone on Fatty Acid Metabolism in HepaRG Cells. Toxicol Sci. 2018 Aug 1;164(2):477-488.
• [21] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [22] Comprehensive transcriptome profiling of BET inhibitor-treated HepG2 cells. PLoS One. 2022 Apr 29;17(4):e0266966. doi: 10.1371/journal.pone.0266966. eCollection 2022.
• [23] New insights into BaP-induced toxicity: role of major metabolites in transcriptomics and contribution to hepatocarcinogenesis. Arch Toxicol. 2016 Jun;90(6):1449-58.
• [24] 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.
• [25] 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.
• [26] Bisphenol A exposure induces metabolic disorders and enhances atherosclerosis in hyperlipidemic rabbits. J Appl Toxicol. 2015 Sep;35(9):1058-70.
• [27] Exendin-4, a glucagon-like peptide-1 receptor agonist, reduces hepatic steatosis and endoplasmic reticulum stress by inducing nuclear factor erythroid-derived 2-related factor 2 nuclear translocation. Toxicol Appl Pharmacol. 2018 Dec 1;360:18-29.
• [28] Effects of dibutyl phthalate on lipid metabolism in liver and hepatocytes based on PPAR/SREBP-1c/FAS/GPAT/AMPK signal pathway. Food Chem Toxicol. 2021 Mar;149:112029. doi: 10.1016/j.fct.2021.112029. Epub 2021 Jan 26.