Details of Drug Off-Target (DOT)

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

• DOT Name: Signal peptidase complex subunit 3 (SPCS3)
• Synonyms: Microsomal signal peptidase 22/23 kDa subunit; SPC22/23; SPase 22/23 kDa subunit
• Gene Name: SPCS3
• Related Disease: Essential tremor
• UniProt ID: SPCS3_HUMAN
• PDB ID: 7P2P; 7P2Q
• Pfam ID: PF04573
• Sequence:
  MNTVLSRANSLFAFSLSVMAALTFGCFITTAFKDRSVPVRLHVSRIMLKNVEDFTGPRER
  SDLGFITFDITADLENIFDWNVKQLFLYLSAEYSTKNNALNQVVLWDKIVLRGDNPKLLL
  KDMKTKYFFFDDGNGLKGNRNVTLTLSWNVVPNAGILPLVTGSGHVSVPFPDTYEITKSY
• Function: Essential component of the signal peptidase complex (SPC) which catalyzes the cleavage of N-terminal signal sequences from nascent proteins as they are translocated into the lumen of the endoplasmic reticulum. Essential for the SPC catalytic activity, possibly by stabilizing and positioning the active center of the complex close to the lumenal surface; (Microbial infection) Plays an important role in virion production of flaviviruses such as West Nile virus, Japanese enchephalitis virus, Dengue virus type 2 and Yellow Fever virus.
• KEGG Pathway: Protein export (hsa03060)
• Reactome Pathway:
  Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) (R-HSA-381771)
  Synthesis, secretion, and inactivation of Glucose-dependent Insulinotropic Polypeptide (GIP) (R-HSA-400511)
  Synthesis, secretion, and deacylation of Ghrelin (R-HSA-422085)
  SRP-dependent cotranslational protein targeting to membrane (R-HSA-1799339)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Essential tremor	DIS7GBKQ	Strong	Genetic Variation	[1]

12 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 Signal peptidase complex subunit 3 (SPCS3).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Signal peptidase complex subunit 3 (SPCS3).	[3]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Signal peptidase complex subunit 3 (SPCS3).	[4]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Signal peptidase complex subunit 3 (SPCS3).	[5]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of Signal peptidase complex subunit 3 (SPCS3).	[6]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Signal peptidase complex subunit 3 (SPCS3).	[7]
APR-246	DMNFADH	Phase 2	APR-246 affects the expression of Signal peptidase complex subunit 3 (SPCS3).	[8]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Signal peptidase complex subunit 3 (SPCS3).	[9]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of Signal peptidase complex subunit 3 (SPCS3).	[10]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Signal peptidase complex subunit 3 (SPCS3).	[11]
[3H]methyltrienolone	DMTSGOW	Investigative	[3H]methyltrienolone increases the expression of Signal peptidase complex subunit 3 (SPCS3).	[12]
Forskolin	DM6ITNG	Investigative	Forskolin increases the expression of Signal peptidase complex subunit 3 (SPCS3).	[12]

References

• [1] Genome-wide association study in essential tremor identifies three new loci.Brain. 2016 Dec;139(Pt 12):3163-3169. doi: 10.1093/brain/aww242. Epub 2016 Oct 20.
• [2] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [3] 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.
• [4] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [5] 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.
• [6] Temporal changes in gene expression in the skin of patients treated with isotretinoin provide insight into its mechanism of action. Dermatoendocrinol. 2009 May;1(3):177-87.
• [7] LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
• [8] Mutant p53 reactivation by PRIMA-1MET induces multiple signaling pathways converging on apoptosis. Oncogene. 2010 Mar 4;29(9):1329-38. doi: 10.1038/onc.2009.425. Epub 2009 Nov 30.
• [9] New insights into BaP-induced toxicity: role of major metabolites in transcriptomics and contribution to hepatocarcinogenesis. Arch Toxicol. 2016 Jun;90(6):1449-58.
• [10] Chemical stresses fail to mimic the unfolded protein response resulting from luminal load with unfolded polypeptides. J Biol Chem. 2018 Apr 13;293(15):5600-5612.
• [11] Bisphenol A Exposure Changes the Transcriptomic and Proteomic Dynamics of Human Retinoblastoma Y79 Cells. Genes (Basel). 2021 Feb 11;12(2):264. doi: 10.3390/genes12020264.
• [12] Identification of genes targeted by the androgen and PKA signaling pathways in prostate cancer cells. Oncogene. 2006 Nov 23;25(55):7311-23.