Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTI1PHMP)

• DOT Name: Signal peptide peptidase-like 2B (SPPL2B)
• Synonyms: SPP-like 2B; SPPL2b; EC 3.4.23.-; Intramembrane protease 4; IMP-4; Presenilin homologous protein 4; PSH4; Presenilin-like protein 1
• Gene Name: SPPL2B
• Related Disease:
  Bacteremia
  Alzheimer disease
  Familial Alzheimer disease
• UniProt ID: SPP2B_HUMAN
• EC Number: 3.4.23.-
• Pfam ID: PF02225 ; PF04258
• Sequence:
  MAAAVAAALARLLAAFLLLAAQVACEYGMVHVVSQAGGPEGKDYCILYNPQWAHLPHDLS
  KASFLQLRNWTASLLCSAADLPARGFSNQIPLVARGNCTFYEKVRLAQGSGARGLLIVSR
  ERLVPPGGNKTQYDEIGIPVALLSYKDMLDIFTRFGRTVRAALYAPKEPVLDYNMVIIFI
  MAVGTVAIGGYWAGSRDVKKRYMKHKRDDGPEKQEDEAVDVTPVMTCVFVVMCCSMLVLL
  YYFYDLLVYVVIGIFCLASATGLYSCLAPCVRRLPFGKCRIPNNSLPYFHKRPQARMLLL
  ALFCVAVSVVWGVFRNEDQWAWVLQDALGIAFCLYMLKTIRLPTFKACTLLLLVLFLYDI
  FFVFITPFLTKSGSSIMVEVATGPSDSATREKLPMVLKVPRLNSSPLALCDRPFSLLGFG
  DILVPGLLVAYCHRFDIQVQSSRVYFVACTIAYGVGLLVTFVALALMQRGQPALLYLVPC
  TLVTSCAVALWRRELGVFWTGSGFAKVLPPSPWAPAPADGPQPPKDSATPLSPQPPSEEP
  ATSPWPAEQSPKSRTSEEMGAGAPMREPGSPAESEGRDQAQPSPVTQPGASA
• Function: Intramembrane-cleaving aspartic protease (I-CLiP) that cleaves type II membrane signal peptides in the hydrophobic plane of the membrane. Functions in ITM2B and TNF processing. Catalyzes the intramembrane cleavage of the anchored fragment of shed TNF-alpha (TNF), which promotes the release of the intracellular domain (ICD) for signaling to the nucleus. May play a role in the regulation of innate and adaptive immunity. Catalyzes the intramembrane cleavage of the simian foamy virus processed leader peptide gp18 of the envelope glycoprotein gp130 dependently of prior ectodomain shedding by furin or furin-like proprotein convertase (PC)-mediated cleavage proteolysis.
• Tissue Specificity: Expressed predominantly in adrenal cortex and mammary gland.
• Reactome Pathway: Regulation of TNFR1 signaling (R-HSA-5357905)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Bacteremia	DIS6N9RZ	Definitive	Biomarker	[1]
Alzheimer disease	DISF8S70	Strong	Biomarker	[2]
Familial Alzheimer disease	DISE75U4	Strong	Genetic Variation	[3]

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 Signal peptide peptidase-like 2B (SPPL2B).	[4]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Signal peptide peptidase-like 2B (SPPL2B).	[6]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Signal peptide peptidase-like 2B (SPPL2B).	[8]

3 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 Signal peptide peptidase-like 2B (SPPL2B).	[5]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Signal peptide peptidase-like 2B (SPPL2B).	[7]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Signal peptide peptidase-like 2B (SPPL2B).	[9]

References

• [1] First reported nosocomial outbreak of Serratia marcescens harboring bla (IMP-4) and bla (VIM-2) in a neonatal intensive care unit in Cairo, Egypt.Infect Drug Resist. 2018 Nov 8;11:2211-2217. doi: 10.2147/IDR.S174869. eCollection 2018.
• [2] BRI2-BRICHOS is increased in human amyloid plaques in early stages of Alzheimer's disease.Neurobiol Aging. 2014 Jul;35(7):1596-604. doi: 10.1016/j.neurobiolaging.2014.01.007. Epub 2014 Jan 13.
• [3] Intramembrane proteolysis of GXGD-type aspartyl proteases is slowed by a familial Alzheimer disease-like mutation.J Biol Chem. 2008 Oct 31;283(44):30121-8. doi: 10.1074/jbc.M806092200. Epub 2008 Sep 3.
• [4] 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.
• [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] 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.
• [7] 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.
• [8] 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.
• [9] Cellular reactions to long-term volatile organic compound (VOC) exposures. Sci Rep. 2016 Dec 1;6:37842. doi: 10.1038/srep37842.