Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTBTMH1Z)

• DOT Name: Serine palmitoyltransferase 2 (SPTLC2)
• Synonyms: EC 2.3.1.50; Long chain base biosynthesis protein 2; LCB 2; Long chain base biosynthesis protein 2a; LCB2a; Serine-palmitoyl-CoA transferase 2; SPT 2
• Gene Name: SPTLC2
• Related Disease:
  Neoplasm
  Neuropathy, hereditary sensory and autonomic, type 1C
  Charcot marie tooth disease
  Hereditary sensory and autonomic neuropathy
  Myocardial infarction
  Peripheral neuropathy
  Riley-Day syndrome
  Hereditary sensory and autonomic neuropathy type 1
  Hepatocellular carcinoma
• UniProt ID: SPTC2_HUMAN
• PDB ID: 6M4N; 6M4O; 7CQI; 7CQK; 7K0I; 7K0J; 7K0K; 7K0L; 7K0M; 7K0N; 7K0O; 7K0P; 7K0Q; 7YIU; 7YIY; 7YJ1; 7YJ2
• EC Number: 2.3.1.50
• Pfam ID: PF00155
• Sequence:
  MRPEPGGCCCRRTVRANGCVANGEVRNGYVRSSAAAAAAAAAGQIHHVTQNGGLYKRPFN
  EAFEETPMLVAVLTYVGYGVLTLFGYLRDFLRYWRIEKCHHATEREEQKDFVSLYQDFEN
  FYTRNLYMRIRDNWNRPICSVPGARVDIMERQSHDYNWSFKYTGNIIKGVINMGSYNYLG
  FARNTGSCQEAAAKVLEEYGAGVCSTRQEIGNLDKHEELEELVARFLGVEAAMAYGMGFA
  TNSMNIPALVGKGCLILSDELNHASLVLGARLSGATIRIFKHNNMQSLEKLLKDAIVYGQ
  PRTRRPWKKILILVEGIYSMEGSIVRLPEVIALKKKYKAYLYLDEAHSIGALGPTGRGVV
  EYFGLDPEDVDVMMGTFTKSFGASGGYIGGKKELIDYLRTHSHSAVYATSLSPPVVEQII
  TSMKCIMGQDGTSLGKECVQQLAENTRYFRRRLKEMGFIIYGNEDSPVVPLMLYMPAKIG
  AFGREMLKRNIGVVVVGFPATPIIESRARFCLSAAHTKEILDTALKEIDEVGDLLQLKYS
  RHRLVPLLDRPFDETTYEETED
• Function: Component of the serine palmitoyltransferase multisubunit enzyme (SPT) that catalyzes the initial and rate-limiting step in sphingolipid biosynthesis by condensing L-serine and activated acyl-CoA (most commonly palmitoyl-CoA) to form long-chain bases. The SPT complex is composed of SPTLC1, SPTLC2 or SPTLC3 and SPTSSA or SPTSSB. Within this complex, the heterodimer consisting of SPTLC1 and SPTLC2/SPTLC3 forms the catalytic core. The composition of the serine palmitoyltransferase (SPT) complex determines the substrate preference. The SPTLC1-SPTLC2-SPTSSA complex shows a strong preference for C16-CoA substrate, while the SPTLC1-SPTLC3-SPTSSA isozyme uses both C14-CoA and C16-CoA as substrates, with a slight preference for C14-CoA. The SPTLC1-SPTLC2-SPTSSB complex shows a strong preference for C18-CoA substrate, while the SPTLC1-SPTLC3-SPTSSB isozyme displays an ability to use a broader range of acyl-CoAs, without apparent preference. Crucial for adipogenesis.
• Tissue Specificity: Widely expressed.
• KEGG Pathway:
  Sphingolipid metabolism (hsa00600)
  Metabolic pathways (hsa01100)
  Sphingolipid sig.ling pathway (hsa04071)
• Reactome Pathway: Sphingolipid de novo biosynthesis (R-HSA-1660661)
• BioCyc Pathway: MetaCyc:HS02117-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

9 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Neoplasm	DISZKGEW	Definitive	Biomarker	[1]
Neuropathy, hereditary sensory and autonomic, type 1C	DISAO9DJ	Definitive	Autosomal dominant	[2]
Charcot marie tooth disease	DIS3BT2L	Strong	Biomarker	[3]
Hereditary sensory and autonomic neuropathy	DIS2VOAM	Strong	Genetic Variation	[4]
Myocardial infarction	DIS655KI	Strong	Genetic Variation	[5]
Peripheral neuropathy	DIS7KN5G	Strong	Genetic Variation	[6]
Riley-Day syndrome	DISJZHNP	Strong	Biomarker	[3]
Hereditary sensory and autonomic neuropathy type 1	DISLSPO4	Supportive	Autosomal dominant	[3]
Hepatocellular carcinoma	DIS0J828	Limited	Biomarker	[7]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cisplatin	DMRHGI9	Approved	Serine palmitoyltransferase 2 (SPTLC2) affects the response to substance of Cisplatin.	[23]

15 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 Serine palmitoyltransferase 2 (SPTLC2).	[8]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Serine palmitoyltransferase 2 (SPTLC2).	[9]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Serine palmitoyltransferase 2 (SPTLC2).	[10]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Serine palmitoyltransferase 2 (SPTLC2).	[11]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Serine palmitoyltransferase 2 (SPTLC2).	[12]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Serine palmitoyltransferase 2 (SPTLC2).	[13]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Serine palmitoyltransferase 2 (SPTLC2).	[14]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Serine palmitoyltransferase 2 (SPTLC2).	[15]
Marinol	DM70IK5	Approved	Marinol increases the expression of Serine palmitoyltransferase 2 (SPTLC2).	[16]
Piroxicam	DMTK234	Approved	Piroxicam decreases the expression of Serine palmitoyltransferase 2 (SPTLC2).	[17]
Liothyronine	DM6IR3P	Approved	Liothyronine increases the expression of Serine palmitoyltransferase 2 (SPTLC2).	[18]
Beta-carotene	DM0RXBT	Approved	Beta-carotene affects the expression of Serine palmitoyltransferase 2 (SPTLC2).	[19]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Serine palmitoyltransferase 2 (SPTLC2).	[20]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Serine palmitoyltransferase 2 (SPTLC2).	[21]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Serine palmitoyltransferase 2 (SPTLC2).	[22]

References

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• [2] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [3] Mutations in the SPTLC2 subunit of serine palmitoyltransferase cause hereditary sensory and autonomic neuropathy type I. Am J Hum Genet. 2010 Oct 8;87(4):513-22. doi: 10.1016/j.ajhg.2010.09.010.
• [4] Hereditary sensory and autonomic neuropathy type IC accompanied by upper motor neuron abnormalities and type II juxtafoveal retinal telangiectasias.J Peripher Nerv Syst. 2019 Jun;24(2):224-229. doi: 10.1111/jns.12315. Epub 2019 Apr 4.
• [5] Increased de novo ceramide synthesis and accumulation in failing myocardium.JCI Insight. 2017 May 4;2(9):e82922. doi: 10.1172/jci.insight.82922. eCollection 2017 May 4.
• [6] Hereditary sensory neuropathy type 1-associated deoxysphingolipids cause neurotoxicity, acute calcium handling abnormalities and mitochondrial dysfunction in vitro.Neurobiol Dis. 2018 Sep;117:1-14. doi: 10.1016/j.nbd.2018.05.008. Epub 2018 May 18.
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• [9] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [10] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [11] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [12] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [13] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [14] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [15] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [16] Genomic and proteomic analysis of the effects of cannabinoids on normal human astrocytes. Brain Res. 2008 Jan 29;1191:1-11.
• [17] Apoptosis induced by piroxicam plus cisplatin combined treatment is triggered by p21 in mesothelioma. PLoS One. 2011;6(8):e23569.
• [18] Monitoring of deiodinase deficiency based on transcriptomic responses in SH-SY5Y cells. Arch Toxicol. 2013 Jun;87(6):1103-13. doi: 10.1007/s00204-013-1018-4. Epub 2013 Feb 10.
• [19] Beta-carotene and apocarotenals promote retinoid signaling in BEAS-2B human bronchioepithelial cells. Arch Biochem Biophys. 2006 Nov 1;455(1):48-60.
• [20] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [21] 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.
• [22] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [23] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.