Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT8OY9ST)

DOT Name	Paraplegin (SPG7)
Synonyms	EC 3.4.24.-; Cell matrix adhesion regulator; Spastic paraplegia 7 protein
Gene Name	SPG7
Related Disease	Hereditary spastic paraplegia 7 ( ) Lymphoma, non-Hodgkin, familial ( ) Non-hodgkin lymphoma ( ) Small lymphocytic lymphoma ( ) Acute lymphocytic leukaemia ( ) Adult glioblastoma ( ) Adult lymphoma ( ) Bladder cancer ( ) Bone osteosarcoma ( ) Craniosynostosis ( ) Epithelial ovarian cancer ( ) Glioblastoma multiforme ( ) Hepatocellular carcinoma ( ) leukaemia ( ) Lung cancer ( ) Lung carcinoma ( ) Lymphoid leukemia ( ) Lymphoma ( ) Melanoma ( ) Metastatic malignant neoplasm ( ) Neuroblastoma ( ) Obesity ( ) Osteosarcoma ( ) Ovarian cancer ( ) Ovarian neoplasm ( ) Paraplegia ( ) Pathologic nystagmus ( ) Pediatric lymphoma ( ) Plasma cell myeloma ( ) Urinary bladder cancer ( ) Urinary bladder neoplasm ( ) Cerebellar ataxia ( ) Childhood acute lymphoblastic leukemia ( ) Lateral sclerosis ( ) Acute myelogenous leukaemia ( ) B-cell lymphoma ( ) B-cell neoplasm ( ) Colorectal carcinoma ( ) Hereditary spastic paraplegia ( ) Leukemia ( ) Mitochondrial disease ( ) Movement disorder ( ) Schizophrenia ( ) Type-1/2 diabetes ( )
UniProt ID	SPG7_HUMAN
3D Structure	Download 2D Sequence (FASTA) Download 3D Structure (PDB) Download
PDB ID	2QZ4
EC Number	3.4.24.-
Pfam ID	PF00004 ; PF17862 ; PF06480 ; PF01434
Sequence	MAVLLLLLRALRRGPGPGPRPLWGPGPAWSPGFPARPGRGRPYMASRPPGDLAEAGGRAL QSLQLRLLTPTFEGINGLLLKQHLVQNPVRLWQLLGGTFYFNTSRLKQKNKEKDKSKGKA PEEDEEERRRRERDDQMYRERLRTLLVIAVVMSLLNALSTSGGSISWNDFVHEMLAKGEV QRVQVVPESDVVEVYLHPGAVVFGRPRLALMYRMQVANIDKFEEKLRAAEDELNIEAKDR IPVSYKRTGFFGNALYSVGMTAVGLAILWYVFRLAGMTGREGGFSAFNQLKMARFTIVDG KMGKGVSFKDVAGMHEAKLEVREFVDYLKSPERFLQLGAKVPKGALLLGPPGCGKTLLAK AVATEAQVPFLAMAGPEFVEVIGGLGAARVRSLFKEARARAPCIVYIDEIDAVGKKRSTT MSGFSNTEEEQTLNQLLVEMDGMGTTDHVIVLASTNRADILDGALMRPGRLDRHVFIDLP TLQERREIFEQHLKSLKLTQSSTFYSQRLAELTPGFSGADIANICNEAALHAAREGHTSV HTLNFEYAVERVLAGTAKKSKILSKEEQKVVAFHESGHALVGWMLEHTEAVMKVSITPRT NAALGFAQMLPRDQHLFTKEQLFERMCMALGGRASEALSFNEVTSGAQDDLRKVTRIAYS MVKQFGMAPGIGPISFPEAQEGLMGIGRRPFSQGLQQMMDHEARLLVAKAYRHTEKVLQD NLDKLQALANALLEKEVINYEDIEALIGPPPHGPKKMIAPQRWIDAQREKQDLGEEETEE TQQPPLGGEEPTWPK
Function	ATP-dependent zinc metalloprotease. Plays a role in the formation and regulation of the mitochondrial permeability transition pore (mPTP) and its proteolytic activity is dispensable for this function.
Tissue Specificity	Ubiquitous.
Reactome Pathway	Processing of SMDT1 (R-HSA-8949664 )

Molecular Interaction Atlas (MIA) of This DOT

44 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance
Hereditary spastic paraplegia 7	DIS4A678	Definitive	Autosomal recessive	[1]
Lymphoma, non-Hodgkin, familial	DISCXYIZ	Definitive	Biomarker	[2]
Non-hodgkin lymphoma	DISS2Y8A	Definitive	Biomarker	[2]
Small lymphocytic lymphoma	DIS30POX	Definitive	Biomarker	[3]
Acute lymphocytic leukaemia	DISPX75S	Strong	Biomarker	[4]
Adult glioblastoma	DISVP4LU	Strong	Biomarker	[5]
Adult lymphoma	DISK8IZR	Strong	Genetic Variation	[6]
Bladder cancer	DISUHNM0	Strong	Biomarker	[7]
Bone osteosarcoma	DIST1004	Strong	Biomarker	[8]
Craniosynostosis	DIS6J405	Strong	Biomarker	[9]
Epithelial ovarian cancer	DIS56MH2	Strong	Biomarker	[10]
Glioblastoma multiforme	DISK8246	Strong	Genetic Variation	[11]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[12]
leukaemia	DISS7D1V	Strong	Biomarker	[13]
Lung cancer	DISCM4YA	Strong	Altered Expression	[14]
Lung carcinoma	DISTR26C	Strong	Altered Expression	[14]
Lymphoid leukemia	DIS65TYQ	Strong	Biomarker	[15]
Lymphoma	DISN6V4S	Strong	Biomarker	[6]
Melanoma	DIS1RRCY	Strong	Biomarker	[16]
Metastatic malignant neoplasm	DIS86UK6	Strong	Biomarker	[17]
Neuroblastoma	DISVZBI4	Strong	Genetic Variation	[18]
Obesity	DIS47Y1K	Strong	Biomarker	[19]
Osteosarcoma	DISLQ7E2	Strong	Biomarker	[8]
Ovarian cancer	DISZJHAP	Strong	Biomarker	[10]
Ovarian neoplasm	DISEAFTY	Strong	Biomarker	[10]
Paraplegia	DISSKWBI	Strong	Biomarker	[20]
Pathologic nystagmus	DIS1QSPO	Strong	CausalMutation	[21]
Pediatric lymphoma	DIS51BK2	Strong	Genetic Variation	[6]
Plasma cell myeloma	DIS0DFZ0	Strong	Biomarker	[22]
Urinary bladder cancer	DISDV4T7	Strong	Biomarker	[7]
Urinary bladder neoplasm	DIS7HACE	Strong	Biomarker	[7]
Cerebellar ataxia	DIS9IRAV	moderate	Genetic Variation	[23]
Childhood acute lymphoblastic leukemia	DISJ5D6U	moderate	Biomarker	[4]
Lateral sclerosis	DISH30B8	Supportive	Autosomal dominant	[24]
Acute myelogenous leukaemia	DISCSPTN	Limited	Biomarker	[25]
B-cell lymphoma	DISIH1YQ	Limited	Biomarker	[26]
B-cell neoplasm	DISVY326	Limited	Biomarker	[27]
Colorectal carcinoma	DIS5PYL0	Limited	Biomarker	[28]
Hereditary spastic paraplegia	DISGZQV1	Limited	Genetic Variation	[29]
Leukemia	DISNAKFL	Limited	Biomarker	[30]
Mitochondrial disease	DISKAHA3	Limited	Genetic Variation	[31]
Movement disorder	DISOJJ2D	Limited	CausalMutation	[32]
Schizophrenia	DISSRV2N	Limited	Genetic Variation	[33]
Type-1/2 diabetes	DISIUHAP	Limited	Biomarker	[19]
------------------------------------------------------------------------------------


⏷ Show the Full List of 44 Disease(s)

Molecular Interaction Atlas (MIA)

MIA Detail

Jump to Detail Molecular Interaction Atlas of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Paraplegin (SPG7).	[34]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Paraplegin (SPG7).	[41]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Paraplegin (SPG7).	[44]
------------------------------------------------------------------------------------

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Paraplegin (SPG7).	[35]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Paraplegin (SPG7).	[36]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Paraplegin (SPG7).	[37]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Paraplegin (SPG7).	[38]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Paraplegin (SPG7).	[39]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Paraplegin (SPG7).	[40]
Selenium	DM25CGV	Approved	Selenium increases the expression of Paraplegin (SPG7).	[42]
Cocaine	DMSOX7I	Approved	Cocaine decreases the expression of Paraplegin (SPG7).	[43]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Paraplegin (SPG7).	[45]
------------------------------------------------------------------------------------


⏷ Show the Full List of 9 Drug(s)

References

1	The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
2	Preclinical Evaluation of Allogeneic CAR T Cells Targeting BCMA for the Treatment of Multiple Myeloma.Mol Ther. 2019 Jun 5;27(6):1126-1138. doi: 10.1016/j.ymthe.2019.04.001. Epub 2019 Apr 8.
3	Safety and tolerability of conditioning chemotherapy followed by CD19-targeted CAR T cells for relapsed/refractory CLL.JCI Insight. 2019 Apr 2;5(9):e122627. doi: 10.1172/jci.insight.122627.
4	Cancer immune therapy for lymphoid malignancies: recent advances.Semin Immunopathol. 2019 Jan;41(1):111-124. doi: 10.1007/s00281-018-0696-7. Epub 2018 Jul 13.
5	CAR-Engineered NK Cells for the Treatment of Glioblastoma: Turning Innate Effectors Into Precision Tools for Cancer Immunotherapy.Front Immunol. 2019 Nov 14;10:2683. doi: 10.3389/fimmu.2019.02683. eCollection 2019.
6	Challenges of driving CD30-directed CAR-T cells to the clinic.BMC Cancer. 2019 Mar 6;19(1):203. doi: 10.1186/s12885-019-5415-9.
7	Targeting CD46 Enhances Anti-Tumoral Activity of Adenovirus Type 5 for Bladder Cancer.Int J Mol Sci. 2018 Sep 10;19(9):2694. doi: 10.3390/ijms19092694.
8	Treating osteosarcoma with CAR T cells.Scand J Immunol. 2019 Mar;89(3):e12741. doi: 10.1111/sji.12741. Epub 2019 Jan 15.
9	Granulocyte-macrophage colony-stimulating factor inactivation in CAR T-cells prevents monocyte-dependent release of key cytokine release syndrome mediators.J Biol Chem. 2019 Apr 5;294(14):5430-5437. doi: 10.1074/jbc.AC119.007558. Epub 2019 Feb 25.
10	Advances Of Chimeric Antigen Receptor T Cell Therapy In Ovarian Cancer.Onco Targets Ther. 2019 Sep 30;12:8015-8022. doi: 10.2147/OTT.S203550. eCollection 2019.
11	Multiparametric magnetic resonance imaging in the assessment of anti-EGFRvIII chimeric antigen receptor T cell therapy in patients with recurrent glioblastoma.Br J Cancer. 2019 Jan;120(1):54-56. doi: 10.1038/s41416-018-0342-0. Epub 2018 Nov 27.
12	Adoptive cell transfer therapy for hepatocellular carcinoma.Front Med. 2019 Feb;13(1):3-11. doi: 10.1007/s11684-019-0684-x. Epub 2019 Jan 18.
13	Allogeneic CAR T cell therapies for leukemia.Am J Hematol. 2019 May;94(S1):S50-S54. doi: 10.1002/ajh.25399. Epub 2019 Feb 1.
14	Cisplatin Synergistically Enhances Antitumor Potency of Conditionally Replicating Adenovirus via p53 Dependent or Independent Pathways in Human Lung Carcinoma.Int J Mol Sci. 2019 Mar 5;20(5):1125. doi: 10.3390/ijms20051125.
15	Induced CD20 Expression on B-Cell Malignant Cells Heightened the Cytotoxic Activity of Chimeric Antigen Receptor Engineered T Cells.Hum Gene Ther. 2019 Apr;30(4):497-510. doi: 10.1089/hum.2018.119. Epub 2019 Jan 23.
16	Combinatorial Approach to Improve Cancer Immunotherapy: Rational Drug Design Strategy to Simultaneously Hit Multiple Targets to Kill Tumor Cells and to Activate the Immune System.J Oncol. 2019 Feb 3;2019:5245034. doi: 10.1155/2019/5245034. eCollection 2019.
17	Pancreatic cancer therapy with combined mesothelin-redirected chimeric antigen receptor T cells and cytokine-armed oncolytic adenoviruses.JCI Insight. 2018 Apr 5;3(7):e99573. doi: 10.1172/jci.insight.99573. eCollection 2018 Apr 5.
18	Efficiency of CAR-T Therapy for Treatment of Solid Tumor in Clinical Trials: A Meta-Analysis.Dis Markers. 2019 Feb 11;2019:3425291. doi: 10.1155/2019/3425291. eCollection 2019.
19	The Role of Xenobiotic Receptors on Hepatic Glycolipid Metabolism.Curr Drug Metab. 2019;20(1):29-35. doi: 10.2174/1389200219666180918152241.
20	Molecular and functional analyses of the human and mouse genes encoding AFG3L1, a mitochondrial metalloprotease homologous to the human spastic paraplegia protein.Genomics. 2001 Aug;76(1-3):58-65. doi: 10.1006/geno.2001.6560.
21	SPG7 mutations explain a significant proportion of French Canadian spastic ataxia cases.Eur J Hum Genet. 2016 Jul;24(7):1016-21. doi: 10.1038/ejhg.2015.240. Epub 2015 Dec 2.
22	Chimeric antigen receptor T cell immunotherapy for multiple myeloma: A review of current data and potential clinical applications.Am J Hematol. 2019 May;94(S1):S28-S33. doi: 10.1002/ajh.25428. Epub 2019 Feb 25.
23	Prevalence and phenotype of the c.1529C>T SPG7 variant in adult-onset cerebellar ataxia in Italy.Eur J Neurol. 2019 Jan;26(1):80-86. doi: 10.1111/ene.13768. Epub 2018 Sep 3.
24	Compound heterozygote mutations in SPG7 in a family with adult-onset primary lateral sclerosis. Neurol Genet. 2016 Mar 3;2(2):e60. doi: 10.1212/NXG.0000000000000060. eCollection 2016 Apr.
25	CAR-T cells beyond CD19, UnCAR-Ted territory.Am J Hematol. 2019 May;94(S1):S34-S41. doi: 10.1002/ajh.25398. Epub 2019 Jan 23.
26	Radiation Priming Chimeric Antigen Receptor T-Cell Therapy in Relapsed/Refractory Diffuse Large B-Cell Lymphoma With High Tumor Burden.J Immunother. 2020 Jan;43(1):32-37. doi: 10.1097/CJI.0000000000000284.
27	T cells redirected against Ig for the immunotherapy of B cell lymphoma.Leukemia. 2020 Mar;34(3):821-830. doi: 10.1038/s41375-019-0607-5. Epub 2019 Oct 17.
28	Combination Therapy with EpCAM-CAR-NK-92 Cells and Regorafenib against Human Colorectal Cancer Models.J Immunol Res. 2018 Oct 15;2018:4263520. doi: 10.1155/2018/4263520. eCollection 2018.
29	m-AAA proteases, mitochondrial calcium homeostasis and neurodegeneration.Cell Res. 2018 Mar;28(3):296-306. doi: 10.1038/cr.2018.17. Epub 2018 Feb 16.
30	Immunotherapy in pediatric B-cell acute lymphoblastic leukemia.Hum Immunol. 2019 Jun;80(6):400-408. doi: 10.1016/j.humimm.2019.01.011. Epub 2019 Feb 1.
31	Causes of progressive cerebellar ataxia: prospective evaluation of 1500 patients.J Neurol Neurosurg Psychiatry. 2017 Apr;88(4):301-309. doi: 10.1136/jnnp-2016-314863. Epub 2016 Dec 13.
32	SMARCA4 inactivating mutations cause concomitant Coffin-Siris syndrome, microphthalmia and small-cell carcinoma of the ovary hypercalcaemic type.J Pathol. 2017 Sep;243(1):9-15. doi: 10.1002/path.4926. Epub 2017 Jul 25.
33	Genome-wide association study of schizophrenia in Ashkenazi Jews.Am J Med Genet B Neuropsychiatr Genet. 2015 Dec;168(8):649-59. doi: 10.1002/ajmg.b.32349. Epub 2015 Jul 21.
34	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.
35	Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
36	Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
37	Increased mitochondrial ROS formation by acetaminophen in human hepatic cells is associated with gene expression changes suggesting disruption of the mitochondrial electron transport chain. Toxicol Lett. 2015 Apr 16;234(2):139-50.
38	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.
39	Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
40	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.
41	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.
42	Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
43	Gene expression in human hippocampus from cocaine abusers identifies genes which regulate extracellular matrix remodeling. PLoS One. 2007 Nov 14;2(11):e1187. doi: 10.1371/journal.pone.0001187.
44	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.
45	Isobaric tags for relative and absolute quantitation-based proteomics analysis of the effect of ginger oil on bisphenol A-induced breast cancer cell proliferation. Oncol Lett. 2021 Feb;21(2):101. doi: 10.3892/ol.2020.12362. Epub 2020 Dec 8.