Details of Drug Off-Target (DOT)

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

• DOT Name: Intermembrane lipid transfer protein VPS13B
• Synonyms: Cohen syndrome protein 1; Vacuolar protein sorting-associated protein 13B
• Gene Name: VPS13B
• Related Disease: Cohen syndrome
• UniProt ID: VP13B_HUMAN
• Pfam ID: PF12624 ; PF16909 ; PF06650
• Sequence:
  MLESYVTPILMSYVNRYIKNLKPSDLQLSLWGGDVVLSKLELKLDVLEQELKLPFTFLSG
  HIHELRIHVPWTKLGSEPVVITINTMECILKLKDGIQDDHESCGSNSTNRSTAESTKSSI
  KPRRMQQAAPTDPDLPPGYVQSLIRRVVNNVNIVINNLILKYVEDDIVLSVNITSAECYT
  VGELWDRAFMDISATDLVLRKVINFSDCTVCLDKRNASGKIEFYQDPLLYKCSFRTRLHF
  TYENLNSKMPSVIKIHTLVESLKLSITDQQLPMFIRIMQLGIALYYGEIGNFKEGEIEDL
  TCHNKDMLGNITGSEDETRIDMQYPAQHKGQELYSQQDEEQPQGWVSWAWSFVPAIVSYD
  DGEEDFVGNDPASTMHQQKAQTLKDPIVSIGFYCTKATVTFKLTEMQVESSYYSPQKVKS
  KEVLCWEQEGTTVEALMMGEPFFDCQIGFVGCRAMCLKGIMGVKDFEENMNRSETEACFF
  ICGDNLSTKGFTYLTNSLFDYRSPENNGTRAEFILDSTHHKETYTEIAGMQRFGAFYMDY
  LYTMENTSGKGSTNQQDFSSGKSEDLGTVQEKSTKSLVIGPLDFRLDSSAVHRILKMIVC
  ALEHEYEPYSRLKSDIKDENETILNPEEVALLEEYIPTRHTSVTLLKCTCTISMAEFNLL
  DHLLPVIMGEKNSSNFMNTTNFQSLRPLPSIRILVDKINLEHSVPMYAEQLVHVVSSLTQ
  PSDNLLHYCYVHCYLKIFGFQAGLTSLDCSGSYCLPVPVIPSFSTALYGKLLKLPTCWTK
  RSQIAITEGIFELPNLTIQATRAQTLLLQAIYQSWSHLGNVSSSAVIEALINEIFLSIGV
  KSKNPLPTLEGSIQNVELKYCSTSLVKCASGTMGSIKICAKAPVDSGKEKLIPLLQGPSD
  TKDLHSTKWLNESRKPESLLAPDLMAFTIQVPQYIDYCHNSGAVLLCSIQGLAVNIDPIL
  YTWLIYQPQKRTSRHMQQQPVVAVPLVMPVCRRKEDEVSIGSAPLAKQQSYQASEYASSP
  VKTKTVTESRPLSVPVKAMLNISESCRSPEERMKEFIGIVWNAVKHLTLQLEVQSCCVFI
  PNDSLPSPSTIVSGDIPGTVRSWYHGQTSMPGTLVLCLPQIKIISAGHKYMEPLQEIPFV
  IPRPILEEGDAFPWTISLHNFSIYTLLGKQVTLCLVEPMGCTSTLAVTSQKLLATGPDTR
  HSFVVCLHVDLESLEIKCSNPQVQLFYELTDIMNKVWNKIQKRGNLNLSPTSPETMAGPV
  PTSPVRSSIGTAPPDTSTCSPSADIGTTTEGDSIQAGEESPFSDSVTLEQTTSNIGGTSG
  RVSLWMQWVLPKITIKLFAPDPENKGTEVCMVSELEDLSASIDVQDVYTKVKCKIESFNI
  DHYRSSLGEECWSLGQCGGVFLSCTDKLNRRTLLVRPISKQDPFSNCSGFFPSTTTKLLD
  GTHQQHGFLSLTYTKAVTKNVRHKLTSRNERRSFHKLSEGLMDGSPHFLHEILLSAQAFD
  IVLYFPLLNAIASIFQAKLPKTQKEKRKSPGQPMRTHTLTSRNLPLIYVNTSVIRIFIPK
  TEEMQPTVEANQAAKEDTVVLKIGSVAMAPQADNPLGRSVLRKDIYQRALNLGILRDPGS
  EIEDRQYQIDLQSINIGTAQWHQLKPEKESVSGGVVTETERNSQNPALEWNMASSIRRHQ
  ERRAILTPVLTDFSVRITGAPAVIFTKVVSPENLHTEEILVCGHSLEVNITTNLDFFLSV
  AQVQLLHQLIVANMTGLEPSNKAAEISKQEQKKVDIFDGGMAETSSRYSGAQDSGIGSDS
  VKIRIVQIEQHSGASQHRIARPSRQSSIVKNLNFIPFDIFITASRISLMTYSCMALSKSK
  SQEQKNNEKTDKSSLNLPEVDSDVAKPNQACISTVTAEDLLRSSISFPSGKKIGVLSLES
  LHASTRSSARQALGITIVRQPGRRGTGDLQLEPFLYFIVSQPSLLLSCHHRKQRVEVSIF
  DAVLKGVASDYKCIDPGKTLPEALDYCTVWLQTVPGEIDSKSGIPPSFITLQIKDFLNGP
  ADVNLDISKPLKANLSFTKLDQINLFLKKIKNAHSLAHSEETSAMSNTMVNKDDLPVSKY
  YRGKLSKPKIHGDGVQKISAQENMWRAVSCFQKISVQTTQIVISMETVPHTSKPCLLASL
  SNLNGSLSVKATQKVPGIILGSSFLLSINDFLLKTSLKERSRILIGPCCATANLEAKWCK
  HSGNPGPEQSIPKISIDLRGGLLQVFWGQEHLNCLVLLHELLNGYLNEEGNFEVQVSEPV
  PQMSSPVEKNQTFKSEQSSDDLRTGLFQYVQDAESLKLPGVYEVLFYNETEDCPGMMLWR
  YPEPRVLTLVRITPVPFNTTEDPDISTADLGDVLQVPCSLEYWDELQKVFVAFREFNLSE
  SKVCELQLPDINLVNDQKKLVSSDLWRIVLNSSQNGADDQSSASESGSQSTCDPLVTPTA
  LAACTRVDSCFTPWFVPSLCVSFQFAHLEFHLCHHLDQLGTAAPQYLQPFVSDRNMPSEL
  EYMIVSFREPHMYLRQWNNGSVCQEIQFLAQADCKLLECRNVTMQSVVKPFSIFGQMAVS
  SDVVEKLLDCTVIVDSVFVNLGQHVVHSLNTAIQAWQQNKCPEVEELVFSHFVICNDTQE
  TLRFGQVDTDENILLASLHSHQYSWRSHKSPQLLHICIEGWGNWRWSEPFSVDHAGTFIR
  TIQYRGRTASLIIKVQQLNGVQKQIIICGRQIICSYLSQSIELKVVQHYIGQDGQAVVRE
  HFDCLTAKQKLPSYILENNELTELCVKAKGDEDWSRDVCLESKAPEYSIVIQVPSSNSSI
  IYVWCTVLTLEPNSQVQQRMIVFSPLFIMRSHLPDPIIIHLEKRSLGLSETQIIPGKGQE
  KPLQNIEPDLVHHLTFQAREEYDPSDCAVPISTSLIKQIATKVHPGGTVNQILDEFYGPE
  KSLQPIWPYNKKDSDRNEQLSQWDSPMRVKLSIWKPYVRTLLIELLPWALLINESKWDLW
  LFEGEKIVLQVPAGKIIIPPNFQEAFQIGIYWANTNTVHKSVAIKLVHNLTSPKWKDGGN
  GEVVTLDEEAFVDTEIRLGAFPGHQKLCQFCISSMVQQGIQIIQIEDKTTIINNTPYQIF
  YKPQLSVCNPHSGKEYFRVPDSATFSICPGGEQPAMKSSSLPCWDLMPDISQSVLDASLL
  QKQIMLGFSPAPGADSSQCWSLPAIVRPEFPRQSVAVPLGNFRENGFCTRAIVLTYQEHL
  GVTYLTLSEDPSPRVIIHNRCPVKMLIKENIKDIPKFEVYCKKIPSECSIHHELYHQISS
  YPDCKTKDLLPSLLLRVEPLDEVTTEWSDAIDINSQGTQVVFLTGFGYVYVDVVHQCGTV
  FITVAPEGKAGPILTNTNRAPEKIVTFKMFITQLSLAVFDDLTHHKASAELLRLTLDNIF
  LCVAPGAGPLPGEEPVAALFELYCVEICCGDLQLDNQLYNKSNFHFAVLVCQGEKAEPIQ
  CSKMQSLLISNKELEEYKEKCFIKLCITLNEGKSILCDINEFSFELKPARLYVEDTFVYY
  IKTLFDTYLPNSRLAGHSTHLSGGKQVLPMQVTQHARALVNPVKLRKLVIQPVNLLVSIH
  ASLKLYIASDHTPLSFSVFERGPIFTTARQLVHALAMHYAAGALFRAGWVVGSLDILGSP
  ASLVRSIGNGVADFFRLPYEGLTRGPGAFVSGVSRGTTSFVKHISKGTLTSITNLATSLA
  RNMDRLSLDEEHYNRQEEWRRQLPESLGEGLRQGLSRLGISLLGAIAGIVDQPMQNFQKT
  SEAQASAGHKAKGVISGVGKGIMGVFTKPIGGAAELVSQTGYGILHGAGLSQLPKQRHQP
  SDLHADQAPNSHVKYVWKMLQSLGRPEVHMALDVVLVRGSGQEHEGCLLLTSEVLFVVSV
  SEDTQQQAFPVTEIDCAQDSKQNNLLTVQLKQPRVACDVEVDGVRERLSEQQYNRLVDYI
  TKTSCHLAPSCSSMQIPCPVVAAEPPPSTVKTYHYLVDPHFAQVFLSKFTMVKNKALRKG
  FP
• Function: Mediates the transfer of lipids between membranes at organelle contact sites. Binds phosphatidylinositol 3-phosphate. Functions as a tethering factor in the slow endocytic recycling pathway, to assist traffic between early and recycling endosomes. Involved in the transport of proacrosomal vesicles to the nuclear dense lamina (NDL) during spermatid development. Plays a role in the assembly of the Golgi apparatus, possibly by mediating trafficking to the Golgi membrane. Plays a role in the development of the nervous system, and may be required for neuron projection development. May also play a role during adipose tissue development. Required for maintenance of the ocular lens.
• Tissue Specificity: Widely expressed . There is apparent differential expression of different transcripts . In fetal brain, lung, liver, and kidney, two transcripts of 2 and 5 kb are identified . These transcripts are also seen in all adult tissues analyzed . A larger transcript (12-14 kb) is expressed in prostate, testis, ovary, and colon in the adult . Expression is very low in adult brain tissue . Expressed in peripheral blood lymphocytes . Isoform 1 and isoform 2 are expressed in brain and retina . Isoform 2 is expressed ubiquitously .

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cohen syndrome	DISOOFEZ	Definitive	Autosomal recessive	[1]

4 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 Intermembrane lipid transfer protein VPS13B.	[2]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Intermembrane lipid transfer protein VPS13B.	[7]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Intermembrane lipid transfer protein VPS13B.	[13]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the methylation of Intermembrane lipid transfer protein VPS13B.	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Intermembrane lipid transfer protein VPS13B.	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Intermembrane lipid transfer protein VPS13B.	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Intermembrane lipid transfer protein VPS13B.	[5]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Intermembrane lipid transfer protein VPS13B.	[6]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Intermembrane lipid transfer protein VPS13B.	[8]
Marinol	DM70IK5	Approved	Marinol increases the expression of Intermembrane lipid transfer protein VPS13B.	[9]
Resveratrol	DM3RWXL	Phase 3	Resveratrol decreases the expression of Intermembrane lipid transfer protein VPS13B.	[10]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of Intermembrane lipid transfer protein VPS13B.	[11]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Intermembrane lipid transfer protein VPS13B.	[12]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Intermembrane lipid transfer protein VPS13B.	[15]

References

• [1] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [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] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [4] 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.
• [5] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [6] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [7] 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.
• [8] The contribution of methotrexate exposure and host factors on transcriptional variance in human liver. Toxicol Sci. 2007 Jun;97(2):582-94.
• [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] A novel long noncoding RNA AK001796 acts as an oncogene and is involved in cell growth inhibition by resveratrol in lung cancer. Toxicol Appl Pharmacol. 2015 Jun 1;285(2):79-88.
• [11] Identification by automated screening of a small molecule that selectively eliminates neural stem cells derived from hESCs but not dopamine neurons. PLoS One. 2009 Sep 23;4(9):e7155.
• [12] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [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] 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] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.