Details of Drug Off-Target (DOT)

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

• DOT Name: Sphingosine kinase 1 (SPHK1)
• Synonyms: SK 1; SPK 1; EC 2.7.1.91; Acetyltransferase SPHK1; EC 2.3.1.-
• Gene Name: SPHK1
• UniProt ID: SPHK1_HUMAN
• PDB ID: 3VZB; 3VZC; 3VZD; 4L02; 4V24
• EC Number: 2.3.1.-; 2.7.1.91
• Pfam ID: PF00781
• Sequence:
  MDPAGGPRGVLPRPCRVLVLLNPRGGKGKALQLFRSHVQPLLAEAEISFTLMLTERRNHA
  RELVRSEELGRWDALVVMSGDGLMHEVVNGLMERPDWETAIQKPLCSLPAGSGNALAASL
  NHYAGYEQVTNEDLLTNCTLLLCRRLLSPMNLLSLHTASGLRLFSVLSLAWGFIADVDLE
  SEKYRRLGEMRFTLGTFLRLAALRTYRGRLAYLPVGRVGSKTPASPVVVQQGPVDAHLVP
  LEEPVPSHWTVVPDEDFVLVLALLHSHLGSEMFAAPMGRCAAGVMHLFYVRAGVSRAMLL
  RLFLAMEKGRHMEYECPYLVYVPVVAFRLEPKDGKGVFAVDGELMVSEAVQGQVHPNYFW
  MVSGCVEPPPSWKPQQMPPPEEPL
• 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-sphingosine and to a lesser extent sphinganine, but not other lipids, such as D,L-threo-dihydrosphingosine, N,N-dimethylsphingosine, diacylglycerol, ceramide, or phosphatidylinositol. In contrast to proapoptotic SPHK2, has a negative effect on intracellular ceramide levels, enhances cell growth and inhibits apoptosis. Involved in the regulation of inflammatory response and neuroinflammation. Via the product sphingosine 1-phosphate, stimulates TRAF2 E3 ubiquitin ligase activity, and promotes activation of NF-kappa-B in response to TNF signaling leading to IL17 secretion. In response to TNF and in parallel to NF-kappa-B activation, negatively regulates RANTES induction through p38 MAPK signaling pathway. Involved in endocytic membrane trafficking induced by sphingosine, recruited to dilate endosomes, also plays a role on later stages of endosomal maturation and membrane fusion independently of its kinase activity. In Purkinje cells, seems to be also involved in the regulation of autophagosome-lysosome fusion upon VEGFA ; Has serine acetyltransferase activity on PTGS2/COX2 in an acetyl-CoA dependent manner. The acetyltransferase activity increases in presence of the kinase substrate, sphingosine. During neuroinflammation, through PTGS2 acetylation, promotes neuronal secretion of specialized preresolving mediators (SPMs), especially 15-R-lipoxin A4, which results in an increase of phagocytic microglia.
• Tissue Specificity: Widely expressed with highest levels in adult liver, kidney, heart and skeletal muscle. Expressed in brain cortex (at protein level) .
• 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:
  Association of TriC/CCT with target proteins during biosynthesis (R-HSA-390471)
  VEGFR2 mediated cell proliferation (R-HSA-5218921)
  Extra-nuclear estrogen signaling (R-HSA-9009391)
  PKR-mediated signaling (R-HSA-9833482)
  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
Afimoxifene	DMFORDT	Phase 2	Sphingosine kinase 1 (SPHK1) decreases the response to substance of Afimoxifene.	[27]

This DOT Affected the Biotransformations of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Sphingosine-1-Phosphate	DMJCQKA	Phase 1	Sphingosine kinase 1 (SPHK1) increases the chemical synthesis of Sphingosine-1-Phosphate.	[28]

2 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 1 (SPHK1).	[1]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Sphingosine kinase 1 (SPHK1).	[9]

30 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 Sphingosine kinase 1 (SPHK1).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Sphingosine kinase 1 (SPHK1).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Sphingosine kinase 1 (SPHK1).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Sphingosine kinase 1 (SPHK1).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Sphingosine kinase 1 (SPHK1).	[6]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Sphingosine kinase 1 (SPHK1).	[7]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Sphingosine kinase 1 (SPHK1).	[8]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Sphingosine kinase 1 (SPHK1).	[10]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Sphingosine kinase 1 (SPHK1).	[11]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Sphingosine kinase 1 (SPHK1).	[12]
Decitabine	DMQL8XJ	Approved	Decitabine increases the expression of Sphingosine kinase 1 (SPHK1).	[13]
Marinol	DM70IK5	Approved	Marinol decreases the expression of Sphingosine kinase 1 (SPHK1).	[14]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Sphingosine kinase 1 (SPHK1).	[15]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Sphingosine kinase 1 (SPHK1).	[16]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Sphingosine kinase 1 (SPHK1).	[10]
Bortezomib	DMNO38U	Approved	Bortezomib decreases the expression of Sphingosine kinase 1 (SPHK1).	[17]
Acocantherin	DM7JT24	Approved	Acocantherin decreases the expression of Sphingosine kinase 1 (SPHK1).	[18]
Resveratrol	DM3RWXL	Phase 3	Resveratrol decreases the expression of Sphingosine kinase 1 (SPHK1).	[19]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Sphingosine kinase 1 (SPHK1).	[20]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Sphingosine kinase 1 (SPHK1).	[21]
F-12509A	DM3786U	Terminated	F-12509A decreases the expression of Sphingosine kinase 1 (SPHK1).	[22]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Sphingosine kinase 1 (SPHK1).	[23]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Sphingosine kinase 1 (SPHK1).	[24]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A decreases the expression of Sphingosine kinase 1 (SPHK1).	[20]
Tributylstannanyl	DMHN7CB	Investigative	Tributylstannanyl decreases the expression of Sphingosine kinase 1 (SPHK1).	[20]
Methyl Mercury Ion	DM6YEW4	Investigative	Methyl Mercury Ion decreases the expression of Sphingosine kinase 1 (SPHK1).	[20]
Hydroxyestradiol	DMJXQME	Investigative	Hydroxyestradiol increases the expression of Sphingosine kinase 1 (SPHK1).	[8]
Nicotinamide-Adenine-Dinucleotide	DM9LRKB	Investigative	Nicotinamide-Adenine-Dinucleotide decreases the activity of Sphingosine kinase 1 (SPHK1).	[25]
DIMETHYLSPINGOSINE	DM1OKN0	Investigative	DIMETHYLSPINGOSINE decreases the activity of Sphingosine kinase 1 (SPHK1).	[26]
VPC-94075	DM20AJ4	Investigative	VPC-94075 decreases the activity of Sphingosine kinase 1 (SPHK1).	[26]

References

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