Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTER78DB)

• DOT Name: Mitochondrial cardiolipin hydrolase (PLD6)
• Synonyms: EC 3.1.4.-; Choline phosphatase 6; Mitochondrial phospholipase; MitoPLD; Phosphatidylcholine-hydrolyzing phospholipase D6; Phospholipase D6; PLD6; Protein zucchini homolog
• Gene Name: PLD6
• Related Disease: Ankylosing spondylitis
• UniProt ID: PLD6_HUMAN
• EC Number: 3.1.4.-
• Pfam ID: PF13091
• Sequence:
  MGRLSWQVAAAAAVGLALTLEALPWVLRWLRSRRRRPRREALFFPSQVTCTEALLRAPGA
  ELAELPEGCPCGLPHGESALSRLLRALLAARASLDLCLFAFSSPQLGRAVQLLHQRGVRV
  RVVTDCDYMALNGSQIGLLRKAGIQVRHDQDPGYMHHKFAIVDKRVLITGSLNWTTQAIQ
  NNRENVLITEDDEYVRLFLEEFERIWEQFNPTKYTFFPPKKSHGSCAPPVSRAGGRLLSW
  HRTCGTSSESQT
• Function: Presents phospholipase and nuclease activities, depending on the different physiological conditions. Interaction with Mitoguardin (MIGA1 or MIGA2) affects the dimer conformation, facilitating the lipase activity over the nuclease activity. Plays a key role in mitochondrial fusion and fission via its phospholipase activity. In its phospholipase role, it uses the mitochondrial lipid cardiolipin as substrate to generate phosphatidate (PA or 1,2-diacyl-sn-glycero-3-phosphate), a second messenger signaling lipid. Production of PA facilitates Mitofusin-mediated fusion, whereas the cleavage of PA by the Lipin family of phosphatases produces diacylgycerol (DAG) which promotes mitochondrial fission. Both Lipin and DAG regulate mitochondrial dynamics and membrane fusion/fission, important processes for adapting mitochondrial metabolism to changes in cell physiology. Mitochondrial fusion enables cells to cope with the increased nucleotide demand during DNA synthesis. Mitochondrial function and dynamics are closely associated with biological processes such as cell growth, proliferation, and differentiation. Mediator of MYC activity, promotes mitochondrial fusion and activates AMPK which in turn inhibits YAP/TAZ, thereby inducing cell growth and proliferation. The endonuclease activity plays a critical role in PIWI-interacting RNA (piRNA) biogenesis during spermatogenesis. Implicated in spermatogenesis and sperm fertility in testicular germ cells, its single strand-specific nuclease activity is critical for the biogenesis/maturation of PIWI-interacting RNA (piRNA). MOV10L1 selectively binds to piRNA precursors and funnels them to the endonuclease that catalyzes the first cleavage step of piRNA processing to generate piRNA intermediate fragments that are subsequently loaded to Piwi proteins. Cleaves either DNA or RNA substrates with similar affinity, producing a 5' phosphate end, in this way it participates in the processing of primary piRNA transcripts. piRNAs provide essential protection against the activity of mobile genetic elements. piRNA-mediated transposon silencing is thus critical for maintaining genome stability, in particular in germline cells when transposons are mobilized as a consequence of wide-spread genomic demethylation. PA may act as signaling molecule in the recognition/transport of the precursor RNAs of primary piRNAs. Interacts with tesmin in testes, suggesting a role in spermatogenesis via association with its interacting partner.
• Tissue Specificity: Predominantly expressed in testis and ovary, but not limited to gonads (at protein level) . It is also found in brain, heart, pituitary gland, prostate, pancreas, thyroid, bone marrow, lung and muscle .
• Reactome Pathway:
  Synthesis of PA (R-HSA-1483166)
  PIWI-interacting RNA (piRNA) biogenesis (R-HSA-5601884)
  Synthesis of PG (R-HSA-1483148)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Ankylosing spondylitis	DISRC6IR	Strong	Biomarker	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Mitochondrial cardiolipin hydrolase (PLD6).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Mitochondrial cardiolipin hydrolase (PLD6).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Mitochondrial cardiolipin hydrolase (PLD6).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Mitochondrial cardiolipin hydrolase (PLD6).	[5]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Mitochondrial cardiolipin hydrolase (PLD6).	[6]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Mitochondrial cardiolipin hydrolase (PLD6).	[7]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Mitochondrial cardiolipin hydrolase (PLD6).	[8]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Mitochondrial cardiolipin hydrolase (PLD6).	[10]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Mitochondrial cardiolipin hydrolase (PLD6).	[11]
Torcetrapib	DMDHYM7	Discontinued in Phase 2	Torcetrapib increases the expression of Mitochondrial cardiolipin hydrolase (PLD6).	[12]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Mitochondrial cardiolipin hydrolase (PLD6).	[13]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of Mitochondrial cardiolipin hydrolase (PLD6).	[14]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane increases the expression of Mitochondrial cardiolipin hydrolase (PLD6).	[15]
ORG2058	DMH1M6N	Investigative	ORG2058 decreases the expression of Mitochondrial cardiolipin hydrolase (PLD6).	[16]

1 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 increases the methylation of Mitochondrial cardiolipin hydrolase (PLD6).	[9]

References

• [1] Genome-wide DNA methylation analysis in ankylosing spondylitis identifies HLA-B*27 dependent and independent DNA methylation changes in whole blood.J Autoimmun. 2019 Aug;102:126-132. doi: 10.1016/j.jaut.2019.04.022. Epub 2019 May 23.
• [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] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [4] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [5] 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.
• [6] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [7] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
• [8] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [9] 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.
• [10] Targeting MYCN in neuroblastoma by BET bromodomain inhibition. Cancer Discov. 2013 Mar;3(3):308-23.
• [11] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [12] Clarifying off-target effects for torcetrapib using network pharmacology and reverse docking approach. BMC Syst Biol. 2012 Dec 10;6:152.
• [13] 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.
• [14] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [15] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.
• [16] The antiproliferative effects of progestins in T47D breast cancer cells are tempered by progestin induction of the ETS transcription factor Elf5. Mol Endocrinol. 2010 Jul;24(7):1380-92. doi: 10.1210/me.2009-0516. Epub 2010 Jun 2.