Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT5GHC9K)

• DOT Name: Intermembrane lipid transfer protein VPS13C
• Synonyms: Vacuolar protein sorting-associated protein 13C
• Gene Name: VPS13C
• Related Disease:
  Autosomal recessive early-onset Parkinson disease 23
  Young-onset Parkinson disease
  Schizophrenia
• UniProt ID: VP13C_HUMAN
• Pfam ID: PF09333 ; PF12624 ; PF21679 ; PF16909 ; PF16908 ; PF16910 ; PF06650
• Sequence:
  MVLESVVADLLNRFLGDYVENLNKSQLKLGIWGGNVALDNLQIKENALSELDVPFKVKAG
  QIDKLTLKIPWKNLYGEAVVATLEGLYLLVVPGASIKYDAVKEEKSLQDVKQKELSRIEE
  ALQKAAEKGTHSGEFIYGLENFVYKDIKPGRKRKKHKKHFKKPFKGLDRSKDKPKEAKKD
  TFVEKLATQVIKNVQVKITDIHIKYEDDVTDPKRPLSFGVTLGELSLLTANEHWTPCILN
  EADKIIYKLIRLDSLSAYWNVNCSMSYQRSREQILDQLKNEILTSGNIPPNYQYIFQPIS
  ASAKLYMNPYAESELKTPKLDCNIEIQNIAIELTKPQYLSMIDLLESVDYMVRNAPYRKY
  KPYLPLHTNGRRWWKYAIDSVLEVHIRRYTQMWSWSNIKKHRQLLKSYKIAYKNKLTQSK
  VSEEIQKEIQDLEKTLDVFNIILARQQAQVEVIRSGQKLRKKSADTGEKRGGWFSGLWGK
  KESKKKDEESLIPETIDDLMTPEEKDKLFTAIGYSESTHNLTLPKQYVAHIMTLKLVSTS
  VTIRENKNIPEILKIQIIGLGTQVSQRPGAQALKVEAKLEHWYITGLRQQDIVPSLVASI
  GDTTSSLLKIKFETNPEDSPADQTLIVQSQPVEVIYDAKTVNAVVEFFQSNKGLDLEQIT
  SATLMKLEEIKERTATGLTHIIETRKVLDLRINLKPSYLVVPQTGFHHEKSDLLILDFGT
  FQLNSKDQGLQKTTNSSLEEIMDKAYDKFDVEIKNVQLLFARAEETWKKCRFQHPSTMHI
  LQPMDIHVELAKAMVEKDIRMARFKVSGGLPLMHVRISDQKMKDVLYLMNSIPLPQKSSA
  QSPERQVSSIPIISGGTKGLLGTSLLLDTVESESDDEYFDAEDGEPQTCKSMKGSELKKA
  AEVPNEELINLLLKFEIKEVILEFTKQQKEEDTILVFNVTQLGTEATMRTFDLTVVSYLK
  KISLDYHEIEGSKRKPLHLISSSDKPGLDLLKVEYIKADKNGPSFQTAFGKTEQTVKVAF
  SSLNLLLQTQALVASINYLTTIIPSDDQSISVAKEVQISTEKQQKNSTLPKAIVSSRDSD
  IIDFRLFAKLNAFCVIVCNEKNNIAEIKIQGLDSSLSLQSRKQSLFARLENIIVTDVDPK
  TVHKKAVSIMGNEVFRFNLDLYPDATEGDLYTDMSKVDGVLSLNVGCIQIVYLHKFLMSL
  LNFLNNFQTAKESLSAATAQAAERAATSVKDLAQRSFRVSINIDLKAPVIVIPQSSISTN
  AVVVDLGLIRVHNQFSLVSDEDYLNPPVIDRMDVQLTKLTLYRTVIQPGIYHPDIQLLHP
  INLEFLVNRNLAASWYHKVPVVEIKGHLDSMNVSLNQEDLNLLFRILTENLCEGTEDLDK
  VKPRVQETGEIKEPLEISISQDVHDSKNTLTTGVEEIRSVDIINMLLNFEIKEVVVTLMK
  KSEKKGRPLHELNVLQLGMEAKVKTYDMTAKAYLKKISMQCFDFTDSKGEPLHIINSSNV
  TDEPLLKMLLTKADSDGPEFKTIHDSTKQRLKVSFASLDLVLHLEALLSFMDFLSSAAPF
  SEPSSSEKESELKPLVGESRSIAVKAVSSNISQKDVFDLKITAELNAFNVFVCDQKCNIA
  DIKIHGMDASISVKPKQTDVFARLKDIIVMNVDLQSIHKKAVSILGDEVFRFQLTLYPDA
  TEGEAYADMSKVDGKLSFKVGCIQIVYVHKFFMSLLNFLNNFQTAKEALSTATVQAAERA
  ASSMKDLAQKSFRLLMDINLKAPVIIIPQSSVSPNAVIADLGLIRVENKFSLVPMEHYSL
  PPVIDKMNIELTQLKLSRTILQASLPQNDIEILKPVNMLLSIQRNLAAAWYVQIPGMEIK
  GKLKPMQVALSEDDLTVLMKILLENLGEASSQPSPTQSVQETVRVRKVDVSSVPDHLKEQ
  EDWTDSKLSMNQIVSLQFDFHFESLSIILYNNDINQESGVAFHNDSFQLGELRLHLMASS
  GKMFKDGSMNVSVKLKTCTLDDLREGIERATSRMIDRKNDQDNNSSMIDISYKQDKNGSQ
  IDAVLDKLYVCASVEFLMTVADFFIKAVPQSPENVAKETQILPRQTATGKVKIEKDDSVR
  PNMTLKAMITDPEVVFVASLTKADAPALTASFQCNLSLSTSKLEQMMEASVRDLKVLACP
  FLREKRGKNITTVLQPCSLFMEKCTWASGKQNINIMVKEFIIKISPIILNTVLTIMAALS
  PKTKEDGSKDTSKEMENLWGIKSINDYNTWFLGVDTATEITESFKGIEHSLIEENCGVVV
  ESIQVTLECGLGHRTVPLLLAESKFSGNIKNWTSLMAAVADVTLQVHYYNEIHAVWEPLI
  ERVEGKRQWNLRLDVKKNPVQDKSLLPGDDFIPEPQMAIHISSGNTMNITISKSCLNVFN
  NLAKGFSEGTASTFDYSLKDRAPFTVKNAVGVPIKVKPNCNLRVMGFPEKSDIFDVDAGQ
  NLELEYASMVPSSQGNLSILSRQESSFFTLTIVPHGYTEVANIPVARPGRRLYNVRNPNA
  SHSDSVLVQIDATEGNKVITLRSPLQIKNHFSIAFIIYKFVKNVKLLERIGIARPEEEFH
  VPLDSYRCQLFIQPAGILEHQYKESTTYISWKEELHRSREVRCMLQCPSVEVSFLPLIVN
  TVALPDELSYICTHGEDWDVAYIIHLYPSLTLRNLLPYSLRYLLEGTAETHELAEGSTAD
  VLHSRISGEIMELVLVKYQGKNWNGHFRIRDTLPEFFPVCFSSDSTEVTTVDLSVHVRRI
  GSRMVLSVFSPYWLINKTTRVLQYRSEDIHVKHPADFRDIILFSFKKKNIFTKNKVQLKI
  STSAWSSSFSLDTVGSYGCVKCPANNMEYLVGVSIKMSSFNLSRIVTLTPFCTIANKSSL
  ELEVGEIASDGSMPTNKWNYIASSECLPFWPESLSGKLCVRVVGCEGSSKPFFYNRQDNG
  TLLSLEDLNGGILVDVNTAEHSTVITFSDYHEGSAPALIMNHTPWDILTYKQSGSPEEMV
  LLPRQARLFAWADPTGTRKLTWTYAANVGEHDLLKDGCGQFPYDANIQIHWVSFLDGRQR
  VLLFTDDVALVSKALQAEEMEQADYEITLSLHSLGLSLVNNESKQEVSYIGITSSGVVWE
  VKPKQKWKPFSQKQIILLEQSYQKHQISRDHGWIKLDNNFEVNFDKDPMEMRLPIRSPIK
  RDFLSGIQIEFKQSSHQRSLRARLYWLQVDNQLPGAMFPVVFHPVAPPKSIALDSEPKPF
  IDVSVITRFNEYSKVLQFKYFMVLIQEMALKIDQGFLGAIIALFTPTTDPEAERRRTKLI
  QQDIDALNAELMETSMTDMSILSFFEHFHISPVKLHLSLSLGSGGEESDKEKQEMFAVHS
  VNLLLKSIGATLTDVDDLIFKLAYYEIRYQFYKRDQLIWSVVRHYSEQFLKQMYVLVLGL
  DVLGNPFGLIRGLSEGVEALFYEPFQGAVQGPEEFAEGLVIGVRSLFGHTVGGAAGVVSR
  ITGSVGKGLAAITMDKEYQQKRREELSRQPRDFGDSLARGGKGFLRGVVGGVTGIITKPV
  EGAKKEGAAGFFKGIGKGLVGAVARPTGGIVDMASSTFQGIQRAAESTEEVSSLRPPRLI
  HEDGIIRPYDRQESEGSDLLENHIKKLEGETYRYHCAIPGSKKTILMVTNRRVLCIKEVE
  ILGLMCVDWQCPFEDFVFPPSVSENVLKISVKEQGLFHKKDSANQGCVRKVYLKDTATAE
  RACNAIEDAQSTRQQQKLMKQSSVRLLRPQLPS
• Function: Mediates the transfer of lipids between membranes at organelle contact sites. Necessary for proper mitochondrial function and maintenance of mitochondrial transmembrane potential. Involved in the regulation of PINK1/PRKN-mediated mitophagy in response to mitochondrial depolarization.
• Tissue Specificity: Widely expressed.

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Autosomal recessive early-onset Parkinson disease 23	DIS45E1R	Strong	Autosomal recessive	[1]
Young-onset Parkinson disease	DIS05LFS	Supportive	Autosomal recessive	[1]
Schizophrenia	DISSRV2N	No Known	Unknown	[2]

13 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 Intermembrane lipid transfer protein VPS13C.	[3]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Intermembrane lipid transfer protein VPS13C.	[4]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Intermembrane lipid transfer protein VPS13C.	[5]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Intermembrane lipid transfer protein VPS13C.	[6]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Intermembrane lipid transfer protein VPS13C.	[7]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Intermembrane lipid transfer protein VPS13C.	[8]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide increases the expression of Intermembrane lipid transfer protein VPS13C.	[10]
Clorgyline	DMCEUJD	Approved	Clorgyline increases the expression of Intermembrane lipid transfer protein VPS13C.	[11]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Intermembrane lipid transfer protein VPS13C.	[12]
Torcetrapib	DMDHYM7	Discontinued in Phase 2	Torcetrapib increases the expression of Intermembrane lipid transfer protein VPS13C.	[14]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Intermembrane lipid transfer protein VPS13C.	[16]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Intermembrane lipid transfer protein VPS13C.	[17]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of Intermembrane lipid transfer protein VPS13C.	[18]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Intermembrane lipid transfer protein VPS13C.	[9]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Intermembrane lipid transfer protein VPS13C.	[13]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Intermembrane lipid transfer protein VPS13C.	[15]

References

• [1] Loss of VPS13C Function in Autosomal-Recessive Parkinsonism Causes Mitochondrial Dysfunction and Increases PINK1/Parkin-Dependent Mitophagy. Am J Hum Genet. 2016 Mar 3;98(3):500-513. doi: 10.1016/j.ajhg.2016.01.014.
• [2] De novo mutations in schizophrenia implicate synaptic networks. Nature. 2014 Feb 13;506(7487):179-84. doi: 10.1038/nature12929. Epub 2014 Jan 22.
• [3] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [4] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [5] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [6] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [7] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [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] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [10] Oxidative stress modulates theophylline effects on steroid responsiveness. Biochem Biophys Res Commun. 2008 Dec 19;377(3):797-802.
• [11] Anti-oncogenic and pro-differentiation effects of clorgyline, a monoamine oxidase A inhibitor, on high grade prostate cancer cells. BMC Med Genomics. 2009 Aug 20;2:55. doi: 10.1186/1755-8794-2-55.
• [12] 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.
• [13] 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.
• [14] Clarifying off-target effects for torcetrapib using network pharmacology and reverse docking approach. BMC Syst Biol. 2012 Dec 10;6:152.
• [15] 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.
• [16] 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.
• [17] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.
• [18] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.