Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTNY3VMD)

• DOT Name: 1-acyl-sn-glycerol-3-phosphate acyltransferase epsilon (AGPAT5)
• Synonyms: EC 2.3.1.51; 1-acylglycerol-3-phosphate O-acyltransferase 5; 1-AGP acyltransferase 5; 1-AGPAT 5; Lysophosphatidic acid acyltransferase epsilon; LPAAT-epsilon
• Gene Name: AGPAT5
• Related Disease: Tourette syndrome
• UniProt ID: PLCE_HUMAN
• EC Number: 2.3.1.51
• Pfam ID: PF16076 ; PF01553
• Sequence:
  MLLSLVLHTYSMRYLLPSVVLLGTAPTYVLAWGVWRLLSAFLPARFYQALDDRLYCVYQS
  MVLFFFENYTGVQILLYGDLPKNKENIIYLANHQSTVDWIVADILAIRQNALGHVRYVLK
  EGLKWLPLYGCYFAQHGGIYVKRSAKFNEKEMRNKLQSYVDAGTPMYLVIFPEGTRYNPE
  QTKVLSASQAFAAQRGLAVLKHVLTPRIKATHVAFDCMKNYLDAIYDVTVVYEGKDDGGQ
  RRESPTMTEFLCKECPKIHIHIDRIDKKDVPEEQEHMRRWLHERFEIKDKMLIEFYESPD
  PERRKRFPGKSVNSKLSIKKTLPSMLILSGLTAGMLMTDAGRKLYVNTWIYGTLLGCLWV
  TIKA
• Function: Converts 1-acyl-sn-glycerol-3-phosphate (lysophosphatidic acid or LPA) into 1,2-diacyl-sn-glycerol-3-phosphate (phosphatidic acid or PA) by incorporating an acyl moiety at the sn-2 position of the glycerol backbone. Acts on LPA containing saturated or unsaturated fatty acids C15:0-C20:4 at the sn-1 position using C18:1-CoA as the acyl donor. Also acts on lysophosphatidylethanolamine using oleoyl-CoA, but not arachidonoyl-CoA, and lysophosphatidylinositol using arachidonoyl-CoA, but not oleoyl-CoA. Activity toward lysophosphatidylglycerol not detectable.
• Tissue Specificity: Widely expressed.
• KEGG Pathway:
  Glycerolipid metabolism (hsa00561)
  Glycerophospholipid metabolism (hsa00564)
  Metabolic pathways (hsa01100)
  Phospholipase D sig.ling pathway (hsa04072)
• Reactome Pathway: Synthesis of PA (R-HSA-1483166)
• BioCyc Pathway: MetaCyc:HS08034-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Tourette syndrome	DISX9D54	Limited	Unknown	[1]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Mitoxantrone	DMM39BF	Approved	1-acyl-sn-glycerol-3-phosphate acyltransferase epsilon (AGPAT5) affects the response to substance of Mitoxantrone.	[17]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of 1-acyl-sn-glycerol-3-phosphate acyltransferase epsilon (AGPAT5).	[2]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of 1-acyl-sn-glycerol-3-phosphate acyltransferase epsilon (AGPAT5).	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of 1-acyl-sn-glycerol-3-phosphate acyltransferase epsilon (AGPAT5).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of 1-acyl-sn-glycerol-3-phosphate acyltransferase epsilon (AGPAT5).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of 1-acyl-sn-glycerol-3-phosphate acyltransferase epsilon (AGPAT5).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of 1-acyl-sn-glycerol-3-phosphate acyltransferase epsilon (AGPAT5).	[6]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of 1-acyl-sn-glycerol-3-phosphate acyltransferase epsilon (AGPAT5).	[7]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of 1-acyl-sn-glycerol-3-phosphate acyltransferase epsilon (AGPAT5).	[8]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of 1-acyl-sn-glycerol-3-phosphate acyltransferase epsilon (AGPAT5).	[9]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of 1-acyl-sn-glycerol-3-phosphate acyltransferase epsilon (AGPAT5).	[10]
Obeticholic acid	DM3Q1SM	Approved	Obeticholic acid decreases the expression of 1-acyl-sn-glycerol-3-phosphate acyltransferase epsilon (AGPAT5).	[11]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of 1-acyl-sn-glycerol-3-phosphate acyltransferase epsilon (AGPAT5).	[12]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of 1-acyl-sn-glycerol-3-phosphate acyltransferase epsilon (AGPAT5).	[13]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of 1-acyl-sn-glycerol-3-phosphate acyltransferase epsilon (AGPAT5).	[15]
methyl p-hydroxybenzoate	DMO58UW	Investigative	methyl p-hydroxybenzoate increases the expression of 1-acyl-sn-glycerol-3-phosphate acyltransferase epsilon (AGPAT5).	[16]

References

• [1] De Novo Coding Variants Are Strongly Associated with Tourette Disorder. Neuron. 2017 May 3;94(3):486-499.e9. doi: 10.1016/j.neuron.2017.04.024.
• [2] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [3] 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.
• [4] 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.
• [5] Increased mitochondrial ROS formation by acetaminophen in human hepatic cells is associated with gene expression changes suggesting disruption of the mitochondrial electron transport chain. Toxicol Lett. 2015 Apr 16;234(2):139-50.
• [6] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [7] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [8] 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.
• [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] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [11] Pharmacotoxicology of clinically-relevant concentrations of obeticholic acid in an organotypic human hepatocyte system. Toxicol In Vitro. 2017 Mar;39:93-103.
• [12] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [13] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [14] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [15] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.
• [16] Transcriptome dynamics of alternative splicing events revealed early phase of apoptosis induced by methylparaben in H1299 human lung carcinoma cells. Arch Toxicol. 2020 Jan;94(1):127-140. doi: 10.1007/s00204-019-02629-w. Epub 2019 Nov 20.
• [17] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.