Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTZSMA54)

• DOT Name: Sphingomyelin phosphodiesterase (SMPD1)
• Synonyms: EC 3.1.4.12; EC 3.1.4.3; Acid sphingomyelinase; aSMase
• Gene Name: SMPD1
• Related Disease:
  Acid sphingomyelinase deficiency
  Niemann-pick disease
  Niemann-Pick disease type A
  Niemann-Pick disease type B
• UniProt ID: ASM_HUMAN
• PDB ID: 5I81; 5I85; 5I8R; 5JG8
• EC Number: 3.1.4.12; 3.1.4.3
• Pfam ID: PF19272 ; PF00149
• Sequence:
  MPRYGASLRQSCPRSGREQGQDGTAGAPGLLWMGLVLALALALALALALSDSRVLWAPAE
  AHPLSPQGHPARLHRIVPRLRDVFGWGNLTCPICKGLFTAINLGLKKEPNVARVGSVAIK
  LCNLLKIAPPAVCQSIVHLFEDDMVEVWRRSVLSPSEACGLLLGSTCGHWDIFSSWNISL
  PTVPKPPPKPPSPPAPGAPVSRILFLTDLHWDHDYLEGTDPDCADPLCCRRGSGLPPASR
  PGAGYWGEYSKCDLPLRTLESLLSGLGPAGPFDMVYWTGDIPAHDVWHQTRQDQLRALTT
  VTALVRKFLGPVPVYPAVGNHESTPVNSFPPPFIEGNHSSRWLYEAMAKAWEPWLPAEAL
  RTLRIGGFYALSPYPGLRLISLNMNFCSRENFWLLINSTDPAGQLQWLVGELQAAEDRGD
  KVHIIGHIPPGHCLKSWSWNYYRIVARYENTLAAQFFGHTHVDEFEVFYDEETLSRPLAV
  AFLAPSATTYIGLNPGYRVYQIDGNYSGSSHVVLDHETYILNLTQANIPGAIPHWQLLYR
  ARETYGLPNTLPTAWHNLVYRMRGDMQLFQTFWFLYHKGHPPSEPCGTPCRLATLCAQLS
  ARADSPALCRHLMPDGSLPEAQSLWPRPLFC
• Function: Converts sphingomyelin to ceramide. Exists as two enzymatic forms that arise from alternative trafficking of a single protein precursor, one that is targeted to the endolysosomal compartment, whereas the other is released extracellularly. However, in response to various forms of stress, lysosomal exocytosis may represent a major source of the secretory form ; In the lysosomes, converts sphingomyelin to ceramide. Plays an important role in the export of cholesterol from the intraendolysosomal membranes. Also has phospholipase C activities toward 1,2-diacylglycerolphosphocholine and 1,2-diacylglycerolphosphoglycerol. Modulates stress-induced apoptosis through the production of ceramide ; When secreted, modulates cell signaling with its ability to reorganize the plasma membrane by converting sphingomyelin to ceramide. Secreted form is increased in response to stress and inflammatory mediators such as IL1B, IFNG or TNF as well as upon infection with bacteria and viruses. Produces the release of ceramide in the outer leaflet of the plasma membrane playing a central role in host defense. Ceramide reorganizes these rafts into larger signaling platforms that are required to internalize P. aeruginosa, induce apoptosis and regulate the cytokine response in infected cells. In wounded cells, the lysosomal form is released extracellularly in the presence of Ca(2+) and promotes endocytosis and plasma membrane repair ; [Sphingomyelin phosphodiesterase, processed form]: This form is generated following cleavage by CASP7 in the extracellular milieu in response to bacterial infection. It shows increased ability to convert sphingomyelin to ceramide and promotes plasma membrane repair. Plasma membrane repair by ceramide counteracts the action of gasdermin-D (GSDMD) perforin (PRF1) pores that are formed in response to bacterial infection; (Microbial infection) Secretion is activated by bacteria such as P. aeruginos, N. gonorrhoeae and others, this activation results in the release of ceramide in the outer leaflet of the plasma membrane which facilitates the infection; (Microbial infection) Secretion is activated by human coronaviruses SARS-CoV and SARS-CoV-2 as well as Zaire ebolavirus, this activation results in the release of ceramide in the outer leaflet of the plasma membrane which facilitates the infection; [Isoform 2]: Lacks residues that bind the cofactor Zn(2+) and has no enzyme activity; [Isoform 3]: Lacks residues that bind the cofactor Zn(2+) and has no enzyme activity.
• KEGG Pathway:
  Sphingolipid metabolism (hsa00600)
  Metabolic pathways (hsa01100)
  Sphingolipid sig.ling pathway (hsa04071)
  Lysosome (hsa04142)
  Necroptosis (hsa04217)
• Reactome Pathway: Glycosphingolipid catabolism (R-HSA-9840310)

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acid sphingomyelinase deficiency	DISD9N88	Definitive	Autosomal recessive	[1]
Niemann-pick disease	DISKS5FO	Definitive	Autosomal recessive	[1]
Niemann-Pick disease type A	DISRCINF	Definitive	Autosomal recessive	[2]
Niemann-Pick disease type B	DISVJCFK	Strong	Autosomal recessive	[3]

24 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 Sphingomyelin phosphodiesterase (SMPD1).	[4]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Sphingomyelin phosphodiesterase (SMPD1).	[5]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Sphingomyelin phosphodiesterase (SMPD1).	[6]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Sphingomyelin phosphodiesterase (SMPD1).	[7]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Sphingomyelin phosphodiesterase (SMPD1).	[8]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Sphingomyelin phosphodiesterase (SMPD1).	[9]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Sphingomyelin phosphodiesterase (SMPD1).	[10]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Sphingomyelin phosphodiesterase (SMPD1).	[11]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Sphingomyelin phosphodiesterase (SMPD1).	[12]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Sphingomyelin phosphodiesterase (SMPD1).	[13]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Sphingomyelin phosphodiesterase (SMPD1).	[14]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Sphingomyelin phosphodiesterase (SMPD1).	[15]
Daunorubicin	DMQUSBT	Approved	Daunorubicin increases the expression of Sphingomyelin phosphodiesterase (SMPD1).	[16]
Fluoxetine	DM3PD2C	Approved	Fluoxetine decreases the activity of Sphingomyelin phosphodiesterase (SMPD1).	[17]
Sevoflurane	DMC9O43	Approved	Sevoflurane decreases the activity of Sphingomyelin phosphodiesterase (SMPD1).	[18]
Desipramine	DMT2FDC	Approved	Desipramine decreases the activity of Sphingomyelin phosphodiesterase (SMPD1).	[19]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Sphingomyelin phosphodiesterase (SMPD1).	[20]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Sphingomyelin phosphodiesterase (SMPD1).	[21]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene increases the expression of Sphingomyelin phosphodiesterase (SMPD1).	[6]
PEITC	DMOMN31	Phase 2	PEITC increases the expression of Sphingomyelin phosphodiesterase (SMPD1).	[22]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Sphingomyelin phosphodiesterase (SMPD1).	[24]
QUERCITRIN	DM1DH96	Investigative	QUERCITRIN increases the expression of Sphingomyelin phosphodiesterase (SMPD1).	[25]
PP-242	DM2348V	Investigative	PP-242 increases the expression of Sphingomyelin phosphodiesterase (SMPD1).	[26]
NSC-106970	DMHK0F6	Investigative	NSC-106970 increases the activity of Sphingomyelin phosphodiesterase (SMPD1).	[27]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Sphingomyelin phosphodiesterase (SMPD1).	[23]

References

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