Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTAUR5TG)

• DOT Name: 1-acyl-sn-glycerol-3-phosphate acyltransferase gamma (AGPAT3)
• Synonyms: EC 2.3.1.51; 1-acylglycerol-3-phosphate O-acyltransferase 3; 1-AGP acyltransferase 3; 1-AGPAT 3; Lysophosphatidic acid acyltransferase gamma; LPAAT-gamma
• Gene Name: AGPAT3
• Related Disease: Chronic obstructive pulmonary disease
• UniProt ID: PLCC_HUMAN
• EC Number: 2.3.1.51
• Pfam ID: PF16076 ; PF01553
• Sequence:
  MGLLAFLKTQFVLHLLVGFVFVVSGLVINFVQLCTLALWPVSKQLYRRLNCRLAYSLWSQ
  LVMLLEWWSCTECTLFTDQATVERFGKEHAVIILNHNFEIDFLCGWTMCERFGVLGSSKV
  LAKKELLYVPLIGWTWYFLEIVFCKRKWEEDRDTVVEGLRRLSDYPEYMWFLLYCEGTRF
  TETKHRVSMEVAAAKGLPVLKYHLLPRTKGFTTAVKCLRGTVAAVYDVTLNFRGNKNPSL
  LGILYGKKYEADMCVRRFPLEDIPLDEKEAAQWLHKLYQEKDALQEIYNQKGMFPGEQFK
  PARRPWTLLNFLSWATILLSPLFSFVLGVFASGSPLLILTFLGFVGAASFGVRRLIGVTE
  IEKGSSYGNQEFKKKE
• 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 C16:0-C20:4 at the sn-1 position using C18:1, C20:4 or C18:2-CoA as the acyl donor. Also acts on lysophosphatidylcholine, lysophosphatidylinositol and lysophosphatidylserine using C18:1 or C20:4-CoA. Has a preference for arachidonoyl-CoA as a donor. Has also a modest lysophosphatidylinositol acyltransferase (LPIAT) activity, converts lysophosphatidylinositol (LPI) into phosphatidylinositol.
• Tissue Specificity: Widely expressed with highest levels in testis, pancreas and kidney, followed by spleen, lung, adipose tissue and liver.
• KEGG Pathway:
  Glycerolipid metabolism (hsa00561)
  Glycerophospholipid metabolism (hsa00564)
  Metabolic pathways (hsa01100)
  Phospholipase D sig.ling pathway (hsa04072)
• Reactome Pathway:
  COPI-independent Golgi-to-ER retrograde traffic (R-HSA-6811436)
  Synthesis of PA (R-HSA-1483166)
• BioCyc Pathway: MetaCyc:HS08470-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
Chronic obstructive pulmonary disease	DISQCIRF	moderate	Biomarker	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of 1-acyl-sn-glycerol-3-phosphate acyltransferase gamma (AGPAT3).	[2]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of 1-acyl-sn-glycerol-3-phosphate acyltransferase gamma (AGPAT3).	[8]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of 1-acyl-sn-glycerol-3-phosphate acyltransferase gamma (AGPAT3).	[12]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of 1-acyl-sn-glycerol-3-phosphate acyltransferase gamma (AGPAT3).	[14]

13 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 1-acyl-sn-glycerol-3-phosphate acyltransferase gamma (AGPAT3).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of 1-acyl-sn-glycerol-3-phosphate acyltransferase gamma (AGPAT3).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of 1-acyl-sn-glycerol-3-phosphate acyltransferase gamma (AGPAT3).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of 1-acyl-sn-glycerol-3-phosphate acyltransferase gamma (AGPAT3).	[6]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of 1-acyl-sn-glycerol-3-phosphate acyltransferase gamma (AGPAT3).	[7]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of 1-acyl-sn-glycerol-3-phosphate acyltransferase gamma (AGPAT3).	[9]
Menadione	DMSJDTY	Approved	Menadione affects the expression of 1-acyl-sn-glycerol-3-phosphate acyltransferase gamma (AGPAT3).	[10]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of 1-acyl-sn-glycerol-3-phosphate acyltransferase gamma (AGPAT3).	[11]
Torcetrapib	DMDHYM7	Discontinued in Phase 2	Torcetrapib increases the expression of 1-acyl-sn-glycerol-3-phosphate acyltransferase gamma (AGPAT3).	[13]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of 1-acyl-sn-glycerol-3-phosphate acyltransferase gamma (AGPAT3).	[15]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of 1-acyl-sn-glycerol-3-phosphate acyltransferase gamma (AGPAT3).	[16]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of 1-acyl-sn-glycerol-3-phosphate acyltransferase gamma (AGPAT3).	[17]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of 1-acyl-sn-glycerol-3-phosphate acyltransferase gamma (AGPAT3).	[18]

References

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• [10] 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.
• [11] 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.
• [12] 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.
• [13] Clarifying off-target effects for torcetrapib using network pharmacology and reverse docking approach. BMC Syst Biol. 2012 Dec 10;6:152.
• [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] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [16] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [17] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [18] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.