Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTZDX6PT)

• DOT Name: Serine palmitoyltransferase 3 (SPTLC3)
• Synonyms: EC 2.3.1.50; Long chain base biosynthesis protein 2b; LCB2b; Long chain base biosynthesis protein 3; LCB 3; Serine-palmitoyl-CoA transferase 3; SPT 3
• Gene Name: SPTLC3
• Related Disease:
  Head-neck squamous cell carcinoma
  Peripheral neuropathy
  Peripheral sensory neuropathies
  Autosomal dominant cerebellar ataxia type II
• UniProt ID: SPTC3_HUMAN
• EC Number: 2.3.1.50
• Pfam ID: PF00155
• Sequence:
  MANPGGGAVCNGKLHNHKKQSNGSQSRNCTKNGIVKEAQQNGKPHFYDKLIVESFEEAPL
  HVMVFTYMGYGIGTLFGYLRDFLRNWGIEKCNAAVERKEQKDFVPLYQDFENFYTRNLYM
  RIRDNWNRPICSAPGPLFDLMERVSDDYNWTFRFTGRVIKDVINMGSYNFLGLAAKYDES
  MRTIKDVLEVYGTGVASTRHEMGTLDKHKELEDLVAKFLNVEAAMVFGMGFATNSMNIPA
  LVGKGCLILSDELNHTSLVLGARLSGATIRIFKHNNTQSLEKLLRDAVIYGQPRTRRAWK
  KILILVEGVYSMEGSIVHLPQIIALKKKYKAYLYIDEAHSIGAVGPTGRGVTEFFGLDPH
  EVDVLMGTFTKSFGASGGYIAGRKDLVDYLRVHSHSAVYASSMSPPIAEQIIRSLKLIMG
  LDGTTQGLQRVQQLAKNTRYFRQRLQEMGFIIYGNENASVVPLLLYMPGKVAAFARHMLE
  KKIGVVVVGFPATPLAEARARFCVSAAHTREMLDTVLEALDEMGDLLQLKYSRHKKSARP
  ELYDETSFELED
• 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.
• Tissue Specificity: Expressed in most tissues, except peripheral blood cells and bone marrow, with highest levels in heart, kidney, liver, uterus and skin.
• 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:HS16070-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Head-neck squamous cell carcinoma	DISF7P24	Strong	Altered Expression	[1]
Peripheral neuropathy	DIS7KN5G	Strong	Genetic Variation	[2]
Peripheral sensory neuropathies	DISYWI6M	Strong	Genetic Variation	[2]
Autosomal dominant cerebellar ataxia type II	DIS0PM39	Limited	Biomarker	[3]

21 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 3 (SPTLC3).	[4]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Serine palmitoyltransferase 3 (SPTLC3).	[5]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Serine palmitoyltransferase 3 (SPTLC3).	[6]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Serine palmitoyltransferase 3 (SPTLC3).	[7]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Serine palmitoyltransferase 3 (SPTLC3).	[8]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Serine palmitoyltransferase 3 (SPTLC3).	[9]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Serine palmitoyltransferase 3 (SPTLC3).	[10]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of Serine palmitoyltransferase 3 (SPTLC3).	[11]
Azathioprine	DMMZSXQ	Approved	Azathioprine decreases the expression of Serine palmitoyltransferase 3 (SPTLC3).	[12]
Cytarabine	DMZD5QR	Approved	Cytarabine decreases the expression of Serine palmitoyltransferase 3 (SPTLC3).	[13]
Nicotine	DMWX5CO	Approved	Nicotine increases the expression of Serine palmitoyltransferase 3 (SPTLC3).	[14]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Serine palmitoyltransferase 3 (SPTLC3).	[15]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of Serine palmitoyltransferase 3 (SPTLC3).	[16]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Serine palmitoyltransferase 3 (SPTLC3).	[5]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Serine palmitoyltransferase 3 (SPTLC3).	[17]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Serine palmitoyltransferase 3 (SPTLC3).	[18]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Serine palmitoyltransferase 3 (SPTLC3).	[19]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Serine palmitoyltransferase 3 (SPTLC3).	[20]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Serine palmitoyltransferase 3 (SPTLC3).	[21]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Serine palmitoyltransferase 3 (SPTLC3).	[22]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of Serine palmitoyltransferase 3 (SPTLC3).	[23]

References

• [1] p38 MAPK mediates epithelial-mesenchymal transition by regulating p38IP and Snail in head and neck squamous cell carcinoma.Oral Oncol. 2016 Sep;60:81-9. doi: 10.1016/j.oraloncology.2016.06.010. Epub 2016 Jul 15.
• [2] Exome Sequence Analysis Suggests that Genetic Burden Contributes to Phenotypic Variability and Complex Neuropathy.Cell Rep. 2015 Aug 18;12(7):1169-83. doi: 10.1016/j.celrep.2015.07.023. Epub 2015 Aug 6.
• [3] Posttranslational modification of ataxin-7 at lysine 257 prevents autophagy-mediated turnover of an N-terminal caspase-7 cleavage fragment.J Neurosci. 2009 Dec 2;29(48):15134-44. doi: 10.1523/JNEUROSCI.4720-09.2009.
• [4] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [5] 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.
• [6] 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.
• [7] 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.
• [8] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [9] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [10] 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.
• [11] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [12] A transcriptomics-based in vitro assay for predicting chemical genotoxicity in vivo. Carcinogenesis. 2012 Jul;33(7):1421-9.
• [13] Cytosine arabinoside induces ectoderm and inhibits mesoderm expression in human embryonic stem cells during multilineage differentiation. Br J Pharmacol. 2011 Apr;162(8):1743-56.
• [14] Characterizing the genetic basis for nicotine induced cancer development: a transcriptome sequencing study. PLoS One. 2013 Jun 18;8(6):e67252.
• [15] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [16] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [17] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [18] 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.
• [19] Bisphenol A and bisphenol S induce distinct transcriptional profiles in differentiating human primary preadipocytes. PLoS One. 2016 Sep 29;11(9):e0163318.
• [20] 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.
• [21] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [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] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.