Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTB4FVP4)

• DOT Name: KICSTOR complex protein SZT2 (SZT2)
• Synonyms: Seizure threshold 2 protein homolog
• Gene Name: SZT2
• Related Disease:
  Developmental and epileptic encephalopathy, 18
  Infantile spasm
  Alzheimer disease
  Cardiovascular disease
  Childhood epilepsy with centrotemporal spikes
  Intellectual disability
  Megalencephaly
  Status epilepticus seizure
  Undetermined early-onset epileptic encephalopathy
  Epilepsy
• UniProt ID: SZT2_HUMAN
• Sequence:
  MASERPEPEVEEAGQVFLLMKKDYRISRNVRLAWFLSHLHQTVQATPQEMLLQSEQELEV
  LSVLPPGWQPDEPVVPRPFLLVPSTRVTFLAWQYRFVIELDLSPSTGIVDDSTGEILFDE
  VFHALSRCLGGLLRPFRVPGSCIDFQPEIYVTIQAYSSIIGLQSHQVLVQGCLLDPSQRE
  VFLQQIYEQLCLFEDKVATMLQQQYDPQSQAEDQSPDSGDLLGRKVGVSMVTADLGLVSM
  IRQGILALQLLPSNSSAGIIVITDGVTSVPDVAVCETLLNQLRSGTVACSFVQVGGVYSY
  DCSFGHVPNVELMKFIAMATFGSYLSTCPEPEPGNLGLTVYHRAFLLYSFLRSGEALNPE
  YYCGSQHRLFNEHLVSASSNPALALRRKKHTEKEVPADLVSTVSVRLREGYSVREVTLAK
  GGSQLEVKLVLLWKHNMRIEYVAMAPWPLEPEGPRVTRVEVTMEGGYDILHDVSCALRQP
  IRSLYRTHVIRRFWNTLQSINQTDQMLAHLQSFSSVPEHFTLPDSTKSGVPLFYIPPGST
  TPVLSLQPSGSDSSHAQFAAYWKPVLSMDANSWQRWLHMHRLVLILEHDTPIPKHLHTPG
  SNGRYSTIQCRISHSSLTSLLRDWSSFVLVEGYSYVKLLSSAPDQPPNSFYMVRIISKAP
  CMVLRLGFPIGTPAPARHKIVSGLREEILRLRFPHRVQSKEPTPKVKRKGLGGAGGGSSP
  SKSPPVLGPQQALSDRPCLVVLHKPLDKLLIRYEKLPLDYRAPFLLTLEPPGPLPLVSGR
  SASSSLASLSRYLYHQRWLWSVPSGLAPALPLSAIAQLLSILTEVRLSEGFHFACSGEGI
  INMVLELPIQNEPPGQAAAEEKHTCVVQYILFPPHSTSTKDSFSTDDDNDVEVEALEGDS
  ELNLVTEVWVEPQYGRVGPGPGIWKHLQDLTYSEIPQALHPRDAACIGSMLSFEYLIQLC
  QSKEWGPLPPEPRVSDGLDQGGDTCVHEIPFHFDLMGLLPQCQQLQMFFLLLAREPEGVP
  FAEGSCPANDMVLCLLHSCLGQELSDREIPLTPVDQAAFLSEVLRRTCHVPGAEGPLLGV
  HGIPKEQAVGSTQATGDSAFTSLSVGLPETLKPLISAQPPQWRCYARLVNPQHVFLTFLP
  ATFSDVQRLAACGLEGPPQEETKPKFGDWSGAPSLKDLGGTGIKATKSHVPVLSVTLASD
  NAQNQGELSPPFRRDLQAYAGRQASQTESADGPRTRCPVYIYSCSLEALREQMVGMQPPQ
  APRDLIFRTQFLDHPSPSSAWMEPRYKEAANHCALLQEHAQRCYVRGLFRSLQQAQSVTS
  QDLLTAVDACEELLQEIDITPFLLALCGHTWGLPHAPPSPGPLSPGPFSSSMEEGAEPRE
  RAILASESSIETEDLSEPEFQSTRVPGIPDPGPEISLTDVCQLRGEAHGALHSVIQEKFL
  EISRLHFRTVPSNPHYFFYCPPSSRREDEGPRDTVDRKISDLEFSEAELMGEEGDTSACC
  VVTESDPELEVEYRESRESDLGPAGLDSASLSDVDTVNPDEDSFSILGGDSPTGPESFLH
  DLPPLFLHLTCSVRLRGQHSSVPVCSLPTCLGQVLSSLEGPPVGGRVPLRDLSVTLDVFM
  LTLPLEVELPTASDPQHHRSTSESSASFPRSPGQPSSLRSDDGLGPPLPPPEEERHPGLS
  NLATPHRLAIETTMNEIRWLLEDEMVGALRRGGIPQSPALHRAAAHIHSSPGRSTCLRQT
  LPLSFVFGPERSLTQFKEEFRRLHLPGHVLLEDPDSGFFFVAAGQQPGGSHGEPSSAAWA
  WHSHEDRAEGIEGETLTASPQAPGSPEDSEGVPLISLPRVPQGGSQPGPSRGLSLMSSQG
  SVDSDHLGYDGGSSGSDSEGPNDTLGEKAPFTLRTPPGPAPPQPSLSGLPGPCLPDFWLI
  VRVLQDRVEVYAHARSLIREDGGPGTECRHLQQLLVRRVGEICREVNQRLLLQDLHDSHV
  CNSLLVAESEEDLWRSETPFHSRQRAPLPSDDYAADESCAPRGYLAATMQFVPGHFSCDV
  VWGTVIRVHSRLKMGPSMGVSRAIQALRSVLNAFSVVNRKNMFVYQERATKAVYYLRLLE
  TSCSDRPWKGDALPPSLALSRSQEPIYSEEASGPRSPLDMVSSRSSDAARPVGQVDRHIQ
  LLVHGVGQAGPEITDELVRVLCRRLDEATLDVITVMLVRNCKLTPADVEFIQPPGSLPSE
  VLHLALPTSCRPWLPALAWYLRQNLLIFLHSPKYTDSNSRNHFQHPLPPQGGLPDLDIYL
  YNKPGGQGTGGKGVACITLAFVDEGGAPLSLALWPPSSPGPPDPLREEEFEQLTQVIRCP
  VVVDSSSAQNGAPRLRLDVWEKGNISIVQLEEKLRGAARQALADAIIELQLLPASLCTED
  TPTGSLRNGSLETKSSAGRASTFPPAPVPGEPVTPPSKAGRRSFWDMLSKTECGDLGSPK
  TTDDIVLDRPEDTRGRRRHKTESVRTPGGAERAPGSDSGAQRQKRRTTQLEEGEVGTLHP
  VFARVAQRWMEFMVQIGCASVSRSSAHMVSRFLLPSILSEFTALVTSMAGDTSVRIFEQH
  LGSEPEIFGPCSPGQLGPSPRPAAERHLLLLGRNFLQWRRPTQQAAKAMQRFEPGGDGSS
  GRNAPRQRLLLLEVVDKKLQLLTYNWAPDLGAALGRALVRLVQWQNARAHLIFCLLSQKL
  GLFHHYGQLDFPVRDEKEPNPFLLPTMEVETLIRSASPPLSREQGRLSGSSRGGGPLPLD
  TFPFDEALRDITAARPSSVLGPVPRPPDPVTYHGQQFLEIKMAERRELERQMKMENLFVT
  WQQRSTPATMPISAGELETLKQSSRLVHYCATAMLFDPAAWLHGPPETSGPPDGQRRHRP
  ESGSGSREAPTSCESLDVSPPGAREEPWLKELSLAFLQQYVQYLQSIGFVLVPLRPPSPA
  RSTSRPRAMAILGTEGRGSFSCPKTKTDGSPKSTSSPVTTYHLQRALPGGIILMELAFQG
  CYFCVKQFALECSRIPMGQAVNSQLSMLFTEECDKVRDLMHVHSFSYDFHLRLVHQHVLG
  AHLVLRHGYHLTTFLRHFLAHHPDGPHFGRNHIYQGTLELPTPLIAAHQLYNYVADHASS
  YHMKPLRMARPGGPEHNEYALVSAWHSSGSYLDSEGLRHQDDFDVSLLVCHCAAPFEEQG
  EAERHVLRLQFFVVLTSQRELFPRLTADMRRFRKPPRLPPEPEAPGSSAGSPGEASGLIL
  APGPAPLFPPLAAEVGMARARLAQLVRLAGGHCRRDTLWKRLFLLEPPGPDRLRLGGRLA
  LAELEELLEAVHAKSIGDIDPQLDCFLSMTVSWYQSLIKVLLSRFPQSCRHFQSPDLGTQ
  YLVVLNQKFTDCFVLVFLDSHLGKTSLTVVFREPFPVQPQDSESPPAQLVSTYHHLESVI
  NTACFTLWTRLL
• Function: As part of the KICSTOR complex functions in the amino acid-sensing branch of the TORC1 signaling pathway. Recruits, in an amino acid-independent manner, the GATOR1 complex to the lysosomal membranes and allows its interaction with GATOR2 and the RAG GTPases. Functions upstream of the RAG GTPases and is required to negatively regulate mTORC1 signaling in absence of amino acids. In absence of the KICSTOR complex mTORC1 is constitutively localized to the lysosome and activated. The KICSTOR complex is also probably involved in the regulation of mTORC1 by glucose. May play a role in the cellular response to oxidative stress.
• Tissue Specificity: Expressed in the brain, predominantly in the parietal and frontal cortex, as well as in dorsal root ganglia. Expressed in peripheral white blood cells.
• Reactome Pathway: Amino acids regulate mTORC1 (R-HSA-9639288)

Molecular Interaction Atlas (MIA) of This DOT

10 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Developmental and epileptic encephalopathy, 18	DISZJRYC	Definitive	Autosomal recessive	[1]
Infantile spasm	DISZSKDG	Definitive	Autosomal recessive	[2]
Alzheimer disease	DISF8S70	Strong	Genetic Variation	[3]
Cardiovascular disease	DIS2IQDX	Strong	Biomarker	[4]
Childhood epilepsy with centrotemporal spikes	DISKT2L5	Strong	CausalMutation	[5]
Intellectual disability	DISMBNXP	Strong	Genetic Variation	[6]
Megalencephaly	DISYW5SV	Strong	Genetic Variation	[6]
Status epilepticus seizure	DISY3BIC	moderate	Genetic Variation	[7]
Undetermined early-onset epileptic encephalopathy	DISISEI2	Supportive	Autosomal dominant	[1]
Epilepsy	DISBB28L	Disputed	Genetic Variation	[6]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the methylation of KICSTOR complex protein SZT2 (SZT2).	[8]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of KICSTOR complex protein SZT2 (SZT2).	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of KICSTOR complex protein SZT2 (SZT2).	[9]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of KICSTOR complex protein SZT2 (SZT2).	[11]

References

• [1] Biallelic SZT2 mutations cause infantile encephalopathy with epilepsy and dysmorphic corpus callosum. Am J Hum Genet. 2013 Sep 5;93(3):524-9. doi: 10.1016/j.ajhg.2013.07.005. Epub 2013 Aug 8.
• [2] 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.
• [3] Family-based association analyses of imputed genotypes reveal genome-wide significant association of Alzheimer's disease with OSBPL6, PTPRG, and PDCL3.Mol Psychiatry. 2016 Nov;21(11):1608-1612. doi: 10.1038/mp.2015.218. Epub 2016 Feb 2.
• [4] Plasma proteomic analysis reveals altered protein abundances in cardiovascular disease.J Transl Med. 2018 Apr 17;16(1):104. doi: 10.1186/s12967-018-1476-9.
• [5] Exome-wide analysis of mutational burden in patients with typical and atypical Rolandic epilepsy.Eur J Hum Genet. 2018 Feb;26(2):258-264. doi: 10.1038/s41431-017-0034-x. Epub 2018 Jan 22.
• [6] Compound heterozygous SZT2 mutations in two siblings with early-onset epilepsy, intellectual disability and macrocephaly.Seizure. 2019 Mar;66:81-85. doi: 10.1016/j.seizure.2018.12.021. Epub 2018 Dec 23.
• [7] Novel SZT2 mutations in three patients with developmental and epileptic encephalopathies.Mol Genet Genomic Med. 2019 Sep;7(9):e926. doi: 10.1002/mgg3.926. Epub 2019 Aug 8.
• [8] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [9] 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.
• [10] 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.
• [11] Environmental pollutant induced cellular injury is reflected in exosomes from placental explants. Placenta. 2020 Jan 1;89:42-49. doi: 10.1016/j.placenta.2019.10.008. Epub 2019 Oct 17.