Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTNFG52M)

• DOT Name: Sphingosine kinase 2 (SPHK2)
• Synonyms: SK 2; SPK 2; EC 2.7.1.91
• Gene Name: SPHK2
• UniProt ID: SPHK2_HUMAN
• EC Number: 2.7.1.91
• Pfam ID: PF00781 ; PF19279
• Sequence:
  MNGHLEAEEQQDQRPDQELTGSWGHGPRSTLVRAKAMAPPPPPLAASTPLLHGEFGSYPA
  RGPRFALTLTSQALHIQRLRPKPEARPRGGLVPLAEVSGCCTLRSRSPSDSAAYFCIYTY
  PRGRRGARRRATRTFRADGAATYEENRAEAQRWATALTCLLRGLPLPGDGEITPDLLPRP
  PRLLLLVNPFGGRGLAWQWCKNHVLPMISEAGLSFNLIQTERQNHARELVQGLSLSEWDG
  IVTVSGDGLLHEVLNGLLDRPDWEEAVKMPVGILPCGSGNALAGAVNQHGGFEPALGLDL
  LLNCSLLLCRGGGHPLDLLSVTLASGSRCFSFLSVAWGFVSDVDIQSERFRALGSARFTL
  GTVLGLATLHTYRGRLSYLPATVEPASPTPAHSLPRAKSELTLTPDPAPPMAHSPLHRSV
  SDLPLPLPQPALASPGSPEPLPILSLNGGGPELAGDWGGAGDAPLSPDPLLSSPPGSPKA
  ALHSPVSEGAPVIPPSSGLPLPTPDARVGASTCGPPDHLLPPLGTPLPPDWVTLEGDFVL
  MLAISPSHLGADLVAAPHARFDDGLVHLCWVRSGISRAALLRLFLAMERGSHFSLGCPQL
  GYAAARAFRLEPLTPRGVLTVDGEQVEYGPLQAQMHPGIGTLLTGPPGCPGREP
• Function: Catalyzes the phosphorylation of sphingosine to form sphingosine-1-phosphate (SPP), a lipid mediator with both intra- and extracellular functions. Also acts on D-erythro-dihydrosphingosine, D-erythro-sphingosine and L-threo-dihydrosphingosine. Binds phosphoinositides. In contrast to prosurvival SPHK1, has a positive effect on intracellular ceramide levels, inhibits cells growth and enhances apoptosis. In mitochondria, is important for cytochrome-c oxidase assembly and mitochondrial respiration. The SPP produced in mitochondria binds PHB2 and modulates the regulation via PHB2 of complex IV assembly and respiration. In nucleus, plays a role in epigenetic regulation of gene expression. Interacts with HDAC1 and HDAC2 and, through SPP production, inhibits their enzymatic activity, preventing the removal of acetyl groups from lysine residues with histones. Up-regulates acetylation of histone H3-K9, histone H4-K5 and histone H2B-K12. In nucleus, may have an inhibitory effect on DNA synthesis and cell cycle. In mast cells, is the main regulator of SPP production which mediates calcium influx, NF-kappa-B activation, cytokine production, such as TNF and IL6, and degranulation of mast cells. In dopaminergic neurons, is involved in promoting mitochondrial functions regulating ATP and ROS levels. Also involved in the regulation of glucose and lipid metabolism.
• Tissue Specificity: Mainly expressed in adult kidney, liver, and brain . Expressed in cerebral cortex and hippocampus (at protein level) . Isoform 1 is the predominant form expressed in most tissues .
• KEGG Pathway:
  Sphingolipid metabolism (hsa00600)
  Metabolic pathways (hsa01100)
  Calcium sig.ling pathway (hsa04020)
  Sphingolipid sig.ling pathway (hsa04071)
  Phospholipase D sig.ling pathway (hsa04072)
  Efferocytosis (hsa04148)
  VEGF sig.ling pathway (hsa04370)
  Apelin sig.ling pathway (hsa04371)
  Fc gamma R-mediated phagocytosis (hsa04666)
  Tuberculosis (hsa05152)
• Reactome Pathway: Sphingolipid de novo biosynthesis (R-HSA-1660661)

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Sphingosine kinase 2 (SPHK2) increases the response to substance of Doxorubicin.	[10]

This DOT Affected the Biotransformations of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
GSK618334	DMJPXZ4	Phase 1	Sphingosine kinase 2 (SPHK2) increases the phosphorylation of GSK618334.	[11]

1 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 Sphingosine kinase 2 (SPHK2).	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Sphingosine kinase 2 (SPHK2).	[2]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Sphingosine kinase 2 (SPHK2).	[3]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Sphingosine kinase 2 (SPHK2).	[4]
Marinol	DM70IK5	Approved	Marinol increases the expression of Sphingosine kinase 2 (SPHK2).	[5]
Cannabidiol	DM0659E	Approved	Cannabidiol increases the expression of Sphingosine kinase 2 (SPHK2).	[6]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Sphingosine kinase 2 (SPHK2).	[7]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Sphingosine kinase 2 (SPHK2).	[8]
GALLICACID	DM6Y3A0	Investigative	GALLICACID increases the expression of Sphingosine kinase 2 (SPHK2).	[9]

References

• [1] 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.
• [2] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [3] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [4] The contribution of methotrexate exposure and host factors on transcriptional variance in human liver. Toxicol Sci. 2007 Jun;97(2):582-94.
• [5] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [6] Cannabidiol Activates Neuronal Precursor Genes in Human Gingival Mesenchymal Stromal Cells. J Cell Biochem. 2017 Jun;118(6):1531-1546. doi: 10.1002/jcb.25815. Epub 2016 Dec 29.
• [7] New insights into BaP-induced toxicity: role of major metabolites in transcriptomics and contribution to hepatocarcinogenesis. Arch Toxicol. 2016 Jun;90(6):1449-58.
• [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] Gene expression profile analysis of gallic acid-induced cell death process. Sci Rep. 2021 Aug 18;11(1):16743. doi: 10.1038/s41598-021-96174-1.
• [10] Involvement of sphingosine kinase 2 in p53-independent induction of p21 by the chemotherapeutic drug doxorubicin. Cancer Res. 2007 Nov 1;67(21):10466-74. doi: 10.1158/0008-5472.CAN-07-2090.
• [11] Active, phosphorylated fingolimod inhibits histone deacetylases and facilitates fear extinction memory. Nat Neurosci. 2014 Jul;17(7):971-80. doi: 10.1038/nn.3728. Epub 2014 May 25.