Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT9X54CQ)

• DOT Name: Sphingosine-1-phosphate phosphatase 1 (SGPP1)
• Synonyms: SPPase1; Spp1; hSPP1; hSPPase1; EC 3.1.3.-; Sphingosine-1-phosphatase 1; Sphingosine-1-phosphate phosphohydrolase 1; SPP-1
• Gene Name: SGPP1
• UniProt ID: SGPP1_HUMAN
• EC Number: 3.1.3.-
• Pfam ID: PF01569
• Sequence:
  MSLRQRLAQLVGRLQDPQKVARFQRLCGVEAPPRRSADRREDEKAEAPLAGDPRLRGRQP
  GAPGGPQPPGSDRNQCPAKPDGGGAPNGVRNGLAAELGPASPRRAGALRRNSLTGEEGQL
  ARVSNWPLYCLFCFGTELGNELFYILFFPFWIWNLDPLVGRRLVVIWVLVMYLGQCTKDI
  IRWPRPASPPVVKLEVFYNSEYSMPSTHAMSGTAIPISMVLLTYGRWQYPLIYGLILIPC
  WCSLVCLSRIYMGMHSILDIIAGFLYTILILAVFYPFVDLIDNFNQTHKYAPFIIIGLHL
  ALGIFSFTLDTWSTSRGDTAEILGSGAGIACGSHVTYNMGLVLDPSLDTLPLAGPPITVT
  LFGKAILRILIGMVFVLIIRDVMKKITIPLACKIFNIPCDDIRKARQHMEVELPYRYITY
  GMVGFSITFFVPYIFFFIGIS
• Function: Specifically dephosphorylates sphingosine 1-phosphate (S1P), dihydro-S1P, and phyto-S1P. Does not act on ceramide 1-phosphate, lysophosphatidic acid or phosphatidic acid. Sphingosine-1-phosphate phosphatase activity is needed for efficient recycling of sphingosine into the sphingolipid synthesis pathway. Regulates the intracellular levels of the bioactive sphingolipid metabolite S1P that regulates diverse biological processes acting both as an extracellular receptor ligand or as an intracellular second messenger. Involved in efficient ceramide synthesis from exogenous sphingoid bases. Converts S1P to sphingosine, which is readily metabolized to ceramide via ceramide synthase. In concert with sphingosine kinase 2 (SphK2), recycles sphingosine into ceramide through a phosphorylation/dephosphorylation cycle. Regulates endoplasmic-to-Golgi trafficking of ceramides, resulting in the regulation of ceramide levels in the endoplasmic reticulum, preferentially long-chain ceramide species, and influences the anterograde membrane transport of both ceramide and proteins from the endoplasmic reticulum to the Golgi apparatus. The modulation of intracellular ceramide levels in turn regulates apoptosis. Via S1P levels, modulates resting tone, intracellular Ca(2+) and myogenic vasoconstriction in resistance arteries. Also involved in unfolded protein response (UPR) and ER stress-induced autophagy via regulation of intracellular S1P levels. Involved in the regulation of epidermal homeostasis and keratinocyte differentiation.
• Tissue Specificity: Ubiquitous, with the strongest level in placenta and kidney.
• KEGG Pathway:
  Sphingolipid metabolism (hsa00600)
  Metabolic pathways (hsa01100)
  Sphingolipid sig.ling pathway (hsa04071)
• Reactome Pathway: Sphingolipid metabolism (R-HSA-428157)

Molecular Interaction Atlas (MIA) of This DOT

10 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 Sphingosine-1-phosphate phosphatase 1 (SGPP1).	[1]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Sphingosine-1-phosphate phosphatase 1 (SGPP1).	[2]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Sphingosine-1-phosphate phosphatase 1 (SGPP1).	[3]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Sphingosine-1-phosphate phosphatase 1 (SGPP1).	[4]
Bortezomib	DMNO38U	Approved	Bortezomib increases the expression of Sphingosine-1-phosphate phosphatase 1 (SGPP1).	[5]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Sphingosine-1-phosphate phosphatase 1 (SGPP1).	[6]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Sphingosine-1-phosphate phosphatase 1 (SGPP1).	[7]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Sphingosine-1-phosphate phosphatase 1 (SGPP1).	[8]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Sphingosine-1-phosphate phosphatase 1 (SGPP1).	[10]
Bilirubin	DMI0V4O	Investigative	Bilirubin decreases the expression of Sphingosine-1-phosphate phosphatase 1 (SGPP1).	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Sphingosine-1-phosphate phosphatase 1 (SGPP1).	[9]

References

• [1] Design principles of concentration-dependent transcriptome deviations in drug-exposed differentiating stem cells. Chem Res Toxicol. 2014 Mar 17;27(3):408-20.
• [2] 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.
• [3] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [4] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [5] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [6] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [7] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [8] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [9] 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.
• [10] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [11] Global changes in gene regulation demonstrate that unconjugated bilirubin is able to upregulate and activate select components of the endoplasmic reticulum stress response pathway. J Biochem Mol Toxicol. 2010 Mar-Apr;24(2):73-88.