Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTCOP0JN)

• DOT Name: Lysocardiolipin acyltransferase 1 (LCLAT1)
• Synonyms: EC 2.3.1.-; 1-acylglycerol-3-phosphate O-acyltransferase 8; 1-AGP acyltransferase 8; 1-AGPAT 8; EC 2.3.1.51; Acyl-CoA:lysocardiolipin acyltransferase 1
• Gene Name: LCLAT1
• Related Disease:
  Parkinson disease
  Pneumonia
  Pneumonitis
  Pulmonary fibrosis
• UniProt ID: LCLT1_HUMAN
• EC Number: 2.3.1.-; 2.3.1.51
• Pfam ID: PF16076 ; PF01553
• Sequence:
  MHSRGREIVVLLNPWSINEAVSSYCTYFIKQDSKSFGIMVSWKGIYFILTLFWGSFFGSI
  FMLSPFLPLMFVNPSWYRWINNRLVATWLTLPVALLETMFGVKVIITGDAFVPGERSVII
  MNHRTRMDWMFLWNCLMRYSYLRLEKICLKASLKGVPGFGWAMQAAAYIFIHRKWKDDKS
  HFEDMIDYFCDIHEPLQLLIFPEGTDLTENSKSRSNAFAEKNGLQKYEYVLHPRTTGFTF
  VVDRLREGKNLDAVHDITVAYPHNIPQSEKHLLQGDFPREIHFHVHRYPIDTLPTSKEDL
  QLWCHKRWEEKEERLRSFYQGEKNFYFTGQSVIPPCKSELRVLVVKLLSILYWTLFSPAM
  CLLIYLYSLVKWYFIITIVIFVLQERIFGGLEIIELACYRLLHKQPHLNSKKNE
• Function: Exhibits acyl-CoA:lysocardiolipin acyltransferase (ALCAT) activity; catalyzes the reacylation of lyso-cardiolipin to cardiolipin (CL), a key step in CL remodeling. Recognizes both monolysocardiolipin and dilysocardiolipin as substrates with a preference for linoleoyl-CoA and oleoyl-CoA as acyl donors. Also exhibits 1-acyl-sn-glycerol-3-phosphate acyltransferase activity (AGPAT) activity; 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. Possesses both lysophosphatidylinositol acyltransferase (LPIAT) and lysophosphatidylglycerol acyltransferase (LPGAT) activities. Required for establishment of the hematopoietic and endothelial lineages.
• Tissue Specificity: Expressed at higher level in heart, kidney and pancreas than in brain, spleen, liver, lung, small intestine and placenta.
• KEGG Pathway:
  Glycerolipid metabolism (hsa00561)
  Glycerophospholipid metabolism (hsa00564)
  Metabolic pathways (hsa01100)
• Reactome Pathway:
  Synthesis of PA (R-HSA-1483166)
  Acyl chain remodeling of CL (R-HSA-1482798)

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Parkinson disease	DISQVHKL	Strong	Biomarker	[1]
Pneumonia	DIS8EF3M	Strong	Altered Expression	[2]
Pneumonitis	DIS88E0K	Strong	Altered Expression	[2]
Pulmonary fibrosis	DISQKVLA	moderate	Biomarker	[3]

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 Lysocardiolipin acyltransferase 1 (LCLAT1).	[4]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Lysocardiolipin acyltransferase 1 (LCLAT1).	[5]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Lysocardiolipin acyltransferase 1 (LCLAT1).	[6]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Lysocardiolipin acyltransferase 1 (LCLAT1).	[7]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Lysocardiolipin acyltransferase 1 (LCLAT1).	[8]
Marinol	DM70IK5	Approved	Marinol increases the expression of Lysocardiolipin acyltransferase 1 (LCLAT1).	[9]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Lysocardiolipin acyltransferase 1 (LCLAT1).	[10]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Lysocardiolipin acyltransferase 1 (LCLAT1).	[11]
GALLICACID	DM6Y3A0	Investigative	GALLICACID decreases the expression of Lysocardiolipin acyltransferase 1 (LCLAT1).	[12]

References

• [1] Cardiolipin remodeling by ALCAT1 links mitochondrial dysfunction to Parkinson's diseases.Aging Cell. 2019 Jun;18(3):e12941. doi: 10.1111/acel.12941. Epub 2019 Mar 5.
• [2] The mitochondrial cardiolipin remodeling enzyme lysocardiolipin acyltransferase is a novel target in pulmonary fibrosis.Am J Respir Crit Care Med. 2014 Jun 1;189(11):1402-15. doi: 10.1164/rccm.201310-1917OC.
• [3] Lysocardiolipin acyltransferase regulates TGF- mediated lung fibroblast differentiation.Free Radic Biol Med. 2017 Nov;112:162-173. doi: 10.1016/j.freeradbiomed.2017.07.023. Epub 2017 Jul 24.
• [4] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [5] 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.
• [6] 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.
• [7] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [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] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [10] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [11] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.
• [12] Gene expression profile analysis of gallic acid-induced cell death process. Sci Rep. 2021 Aug 18;11(1):16743. doi: 10.1038/s41598-021-96174-1.