Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTIVOS2I)

• DOT Name: Spartin (SPART)
• Synonyms: Spastic paraplegia 20 protein; Trans-activated by hepatitis C virus core protein 1
• Gene Name: SPART
• Related Disease:
  46,XY sex reversal 11
  Hepatocellular carcinoma
  Troyer syndrome
  Adenoma
  Adult lymphoma
  B-cell lymphoma
  Colorectal carcinoma
  Follicular lymphoma
  Gastric cancer
  Hereditary spastic paraplegia
  Lymphoma
  Neoplasm
  Neuroblastoma
  Pediatric lymphoma
  Stomach cancer
  Vascular purpura
  Advanced cancer
  Esophageal adenocarcinoma
  Gastritis
• UniProt ID: SPART_HUMAN
• PDB ID: 2DL1; 4U7I
• Pfam ID: PF06911
• Sequence:
  MEQEPQNGEPAEIKIIREAYKKAFLFVNKGLNTDELGQKEEAKNYYKQGIGHLLRGISIS
  SKESEHTGPGWESARQMQQKMKETLQNVRTRLEILEKGLATSLQNDLQEVPKLYPEFPPK
  DMCEKLPEPQSFSSAPQHAEVNGNTSTPSAGAVAAPASLSLPSQSCPAEAPPAYTPQAAE
  GHYTVSYGTDSGEFSSVGEEFYRNHSQPPPLETLGLDADELILIPNGVQIFFVNPAGEVS
  APSYPGYLRIVRFLDNSLDTVLNRPPGFLQVCDWLYPLVPDRSPVLKCTAGAYMFPDTML
  QAAGCFVGVVLSSELPEDDRELFEDLLRQMSDLRLQANWNRAEEENEFQIPGRTRPSSDQ
  LKEASGTDVKQLDQGNKDVRHKGKRGKRAKDTSSEEVNLSHIVPCEPVPEEKPKELPEWS
  EKVAHNILSGASWVSWGLVKGAEITGKAIQKGASKLRERIQPEEKPVEVSPAVTKGLYIA
  KQATGGAAKVSQFLVDGVCTVANCVGKELAPHVKKHGSKLVPESLKKDKDGKSPLDGAMV
  VAASSVQGFSTVWQGLECAAKCIVNNVSAETVQTVRYKYGYNAGEATHHAVDSAVNVGVT
  AYNINNIGIKAMVKKTATQTGHTLLEDYQIVDNSQRENQEGAANVNVRGEKDEQTKEVKE
  AKKKDK
• Function: May be implicated in endosomal trafficking, or microtubule dynamics, or both. Participates in cytokinesis.
• Tissue Specificity: Ubiquitously expressed, with highest levels of expression detected in adipose tissue.
• KEGG Pathway: Endocytosis (hsa04144)

Molecular Interaction Atlas (MIA) of This DOT

19 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
46,XY sex reversal 11	DISYJTLT	Definitive	Genetic Variation	[1]
Hepatocellular carcinoma	DIS0J828	Definitive	Altered Expression	[2]
Troyer syndrome	DISA9RYJ	Definitive	Autosomal recessive	[3]
Adenoma	DIS78ZEV	Strong	Posttranslational Modification	[4]
Adult lymphoma	DISK8IZR	Strong	Biomarker	[5]
B-cell lymphoma	DISIH1YQ	Strong	Posttranslational Modification	[6]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[7]
Follicular lymphoma	DISVEUR6	Strong	Posttranslational Modification	[6]
Gastric cancer	DISXGOUK	Strong	Biomarker	[8]
Hereditary spastic paraplegia	DISGZQV1	Strong	Genetic Variation	[9]
Lymphoma	DISN6V4S	Strong	Biomarker	[5]
Neoplasm	DISZKGEW	Strong	Altered Expression	[2]
Neuroblastoma	DISVZBI4	Strong	Altered Expression	[10]
Pediatric lymphoma	DIS51BK2	Strong	Biomarker	[5]
Stomach cancer	DISKIJSX	Strong	Biomarker	[8]
Vascular purpura	DIS6ZZMF	Strong	Genetic Variation	[9]
Advanced cancer	DISAT1Z9	moderate	Biomarker	[5]
Esophageal adenocarcinoma	DISODWFP	moderate	Biomarker	[11]
Gastritis	DIS8G07K	Limited	Posttranslational Modification	[8]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Methotrexate	DM2TEOL	Approved	Spartin (SPART) affects the response to substance of Methotrexate.	[24]

11 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 Spartin (SPART).	[12]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Spartin (SPART).	[13]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Spartin (SPART).	[14]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Spartin (SPART).	[15]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Spartin (SPART).	[16]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Spartin (SPART).	[17]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of Spartin (SPART).	[18]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Spartin (SPART).	[21]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of Spartin (SPART).	[22]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of Spartin (SPART).	[16]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A increases the expression of Spartin (SPART).	[23]

2 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 affects the methylation of Spartin (SPART).	[19]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Spartin (SPART).	[20]

References

• [1] SPG20 is mutated in Troyer syndrome, an hereditary spastic paraplegia. Nat Genet. 2002 Aug;31(4):347-8. doi: 10.1038/ng937. Epub 2002 Jul 22.
• [2] Aberrant methylation status of SPG20 promoter in hepatocellular carcinoma: A potential tumor metastasis biomarker.Cancer Genet. 2019 Apr;233-234:48-55. doi: 10.1016/j.cancergen.2019.04.003. Epub 2019 Apr 12.
• [3] 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.
• [4] SPG20, a novel biomarker for early detection of colorectal cancer, encodes a regulator of cytokinesis.Oncogene. 2011 Sep 15;30(37):3967-78. doi: 10.1038/onc.2011.109. Epub 2011 Apr 18.
• [5] Colorectal cancer DNA methylation marker panel validated with high performance in Non-Hodgkin lymphoma.Epigenetics. 2014 Mar;9(3):428-36. doi: 10.4161/epi.27554. Epub 2013 Dec 20.
• [6] Methylation changes of SIRT1, KLF4, DAPK1 and SPG20 in B-lymphocytes derived from follicular and diffuse large B-cell lymphoma.Leuk Res. 2017 Jun;57:89-96. doi: 10.1016/j.leukres.2017.02.012. Epub 2017 Mar 9.
• [7] Detection of SPG20 gene promoter-methylated DNA, as a novel epigenetic biomarker, in plasma for colorectal cancer diagnosis using the MethyLight method.Oncol Lett. 2017 May;13(5):3277-3284. doi: 10.3892/ol.2017.5815. Epub 2017 Mar 7.
• [8] Methylomics analysis identifies a putative STAT3 target, SPG20, as a noninvasive epigenetic biomarker for early detection of gastric cancer.PLoS One. 2019 Jun 13;14(6):e0218338. doi: 10.1371/journal.pone.0218338. eCollection 2019.
• [9] Three cases of Troyer syndrome in two families of Filipino descent.Am J Med Genet A. 2016 Jul;170(7):1780-5. doi: 10.1002/ajmg.a.37658. Epub 2016 Apr 26.
• [10] Different expression levels of spartin cause broad spectrum of cellular consequences in human neuroblastoma cells.Cell Biol Int. 2015 Sep;39(9):1007-15. doi: 10.1002/cbin.10472. Epub 2015 May 8.
• [11] Exome and whole-genome sequencing of esophageal adenocarcinoma identifies recurrent driver events and mutational complexity.Nat Genet. 2013 May;45(5):478-86. doi: 10.1038/ng.2591. Epub 2013 Mar 24.
• [12] 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.
• [13] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [14] 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.
• [15] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [16] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [17] 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.
• [18] Zoledronate dysregulates fatty acid metabolism in renal tubular epithelial cells to induce nephrotoxicity. Arch Toxicol. 2018 Jan;92(1):469-485.
• [19] 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.
• [20] 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.
• [21] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [22] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [23] Persistence of epigenomic effects after recovery from repeated treatment with two nephrocarcinogens. Front Genet. 2018 Dec 3;9:558.
• [24] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.