Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTN0Z98K)

• DOT Name: Serine palmitoyltransferase 1 (SPTLC1)
• Synonyms: EC 2.3.1.50; Long chain base biosynthesis protein 1; LCB 1; Serine-palmitoyl-CoA transferase 1; SPT 1; SPT1
• Gene Name: SPTLC1
• Related Disease:
  Non-insulin dependent diabetes
  Advanced cancer
  Amyotrophic lateral sclerosis 27, juvenile
  Autonomic nervous system disorder
  Charcot marie tooth disease
  Charcot-Marie-Tooth disease type 2
  Charcot-Marie-Tooth disease type 2B
  Dementia
  Dysautonomia
  Hereditary motor and sensory neuropathy
  Hereditary sensory and autonomic neuropathy
  Huntington disease
  Keratosis
  Multiple self-healing squamous epithelioma
  Neuropathy, hereditary sensory and autonomic, type 1A
  Peripheral neuropathy
  Renal cell carcinoma
  Riley-Day syndrome
  Bipolar disorder
  Clear cell renal carcinoma
  Neoplasm
  Peripheral sensory neuropathies
  Psychotic disorder
  Schizophrenia
  Hereditary sensory and autonomic neuropathy type 1
  Brain cancer
  Brain neoplasm
  Frontotemporal dementia
  Glioma
  Mental disorder
  Nervous system disease
• UniProt ID: SPTC1_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:
  MATATEQWVLVEMVQALYEAPAYHLILEGILILWIIRLLFSKTYKLQERSDLTVKEKEEL
  IEEWQPEPLVPPVPKDHPALNYNIVSGPPSHKTVVNGKECINFASFNFLGLLDNPRVKAA
  ALASLKKYGVGTCGPRGFYGTFDVHLDLEDRLAKFMKTEEAIIYSYGFATIASAIPAYSK
  RGDIVFVDRAACFAIQKGLQASRSDIKLFKHNDMADLERLLKEQEIEDQKNPRKARVTRR
  FIVVEGLYMNTGTICPLPELVKLKYKYKARIFLEESLSFGVLGEHGRGVTEHYGINIDDI
  DLISANMENALASIGGFCCGRSFVIDHQRLSGQGYCFSASLPPLLAAAAIEALNIMEENP
  GIFAVLKEKCGQIHKALQGISGLKVVGESLSPAFHLQLEESTGSREQDVRLLQEIVDQCM
  NRSIALTQARYLEKEEKCLPPPSIRVVVTVEQTEEELERAASTIKEVAQAVLL
• 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 also composed of SPTLC2 or SPTLC3 and SPTSSA or SPTSSB. Within this complex, the heterodimer with SPTLC2 or 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. Required for adipocyte cell viability and metabolic homeostasis.
• Tissue Specificity: Widely expressed. Not detected in small intestine.
• 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:HS01673-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

31 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Non-insulin dependent diabetes	DISK1O5Z	Definitive	Biomarker	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Amyotrophic lateral sclerosis 27, juvenile	DIS8XE44	Strong	Autosomal dominant	[3]
Autonomic nervous system disorder	DIS6JLTA	Strong	Biomarker	[4]
Charcot marie tooth disease	DIS3BT2L	Strong	Biomarker	[5]
Charcot-Marie-Tooth disease type 2	DISR30O9	Strong	Biomarker	[6]
Charcot-Marie-Tooth disease type 2B	DIS00RWZ	Strong	Genetic Variation	[7]
Dementia	DISXL1WY	Strong	Biomarker	[8]
Dysautonomia	DISF4MT6	Strong	Biomarker	[4]
Hereditary motor and sensory neuropathy	DISR0X2K	Strong	Genetic Variation	[9]
Hereditary sensory and autonomic neuropathy	DIS2VOAM	Strong	Genetic Variation	[10]
Huntington disease	DISQPLA4	Strong	Altered Expression	[11]
Keratosis	DISF0NF1	Strong	Genetic Variation	[12]
Multiple self-healing squamous epithelioma	DISPYT7K	Strong	Biomarker	[13]
Neuropathy, hereditary sensory and autonomic, type 1A	DISXOLQ1	Strong	Autosomal dominant	[14]
Peripheral neuropathy	DIS7KN5G	Strong	Genetic Variation	[15]
Renal cell carcinoma	DISQZ2X8	Strong	Biomarker	[16]
Riley-Day syndrome	DISJZHNP	Strong	Biomarker	[5]
Bipolar disorder	DISAM7J2	moderate	Genetic Variation	[17]
Clear cell renal carcinoma	DISBXRFJ	moderate	Altered Expression	[18]
Neoplasm	DISZKGEW	moderate	Biomarker	[18]
Peripheral sensory neuropathies	DISYWI6M	moderate	Genetic Variation	[19]
Psychotic disorder	DIS4UQOT	moderate	Genetic Variation	[17]
Schizophrenia	DISSRV2N	moderate	Genetic Variation	[17]
Hereditary sensory and autonomic neuropathy type 1	DISLSPO4	Supportive	Autosomal dominant	[14]
Brain cancer	DISBKFB7	Limited	Biomarker	[20]
Brain neoplasm	DISY3EKS	Limited	Biomarker	[20]
Frontotemporal dementia	DISKYHXL	Limited	Biomarker	[8]
Glioma	DIS5RPEH	Limited	Genetic Variation	[20]
Mental disorder	DIS3J5R8	Limited	Genetic Variation	[17]
Nervous system disease	DISJ7GGT	Limited	Biomarker	[21]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Serine palmitoyltransferase 1 (SPTLC1).	[22]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Serine palmitoyltransferase 1 (SPTLC1).	[23]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Serine palmitoyltransferase 1 (SPTLC1).	[24]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Serine palmitoyltransferase 1 (SPTLC1).	[25]
Marinol	DM70IK5	Approved	Marinol increases the expression of Serine palmitoyltransferase 1 (SPTLC1).	[26]
Clozapine	DMFC71L	Approved	Clozapine decreases the expression of Serine palmitoyltransferase 1 (SPTLC1).	[27]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Serine palmitoyltransferase 1 (SPTLC1).	[28]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Serine palmitoyltransferase 1 (SPTLC1).	[29]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of Serine palmitoyltransferase 1 (SPTLC1).	[30]
KOJIC ACID	DMP84CS	Investigative	KOJIC ACID increases the expression of Serine palmitoyltransferase 1 (SPTLC1).	[31]

References

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• [2] The human homologue of the ninjurin gene maps to the candidate region of hereditary sensory neuropathy type I (HSNI).Genomics. 1998 Jan 1;47(1):58-63. doi: 10.1006/geno.1997.5084.
• [3] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [4] Two novel mutations of SCN9A (Nav1.7) are associated with partial congenital insensitivity to pain.Eur J Pain. 2011 Mar;15(3):223-30. doi: 10.1016/j.ejpain.2010.07.003. Epub 2010 Aug 7.
• [5] V144D Mutation of SPTLC1 Can Present with Both Painful and Painless Phenotypes in Hereditary Sensory and Autonomic Neuropathies Type I.Case Rep Genet. 2018 Oct 18;2018:1898151. doi: 10.1155/2018/1898151. eCollection 2018.
• [6] Hereditary sensory neuropathy type 1 is caused by the accumulation of two neurotoxic sphingolipids.J Biol Chem. 2010 Apr 9;285(15):11178-87. doi: 10.1074/jbc.M109.092973. Epub 2010 Jan 22.
• [7] Hereditary sensory neuropathies.Drugs Today (Barc). 2004 May;40(5):385-94. doi: 10.1358/dot.2004.40.5.850487.
• [8] DNMT1 mutation hot spot causes varied phenotypes of HSAN1 with dementia and hearing loss.Neurology. 2013 Feb 26;80(9):824-8. doi: 10.1212/WNL.0b013e318284076d. Epub 2013 Jan 30.
• [9] Targeted high-throughput sequencing identifies mutations in atlastin-1 as a cause of hereditary sensory neuropathy type I. Am J Hum Genet. 2011 Jan 7;88(1):99-105. doi: 10.1016/j.ajhg.2010.12.003. Epub 2010 Dec 30.
• [10] The Variant p.(Arg183Trp) in SPTLC2 Causes Late-Onset Hereditary Sensory Neuropathy.Neuromolecular Med. 2016 Mar;18(1):81-90. doi: 10.1007/s12017-015-8379-1. Epub 2015 Nov 16.
• [11] De novo Synthesis of Sphingolipids Is Defective in Experimental Models of Huntington's Disease.Front Neurosci. 2017 Dec 19;11:698. doi: 10.3389/fnins.2017.00698. eCollection 2017.
• [12] Exclusion of serine palmitoyltransferase long chain base subunit 2 (SPTLC2) as a common cause for hereditary sensory neuropathy.Neuromuscul Disord. 2002 Oct;12(7-8):656-8. doi: 10.1016/s0960-8966(02)00015-9.
• [13] A YAC-based transcript map of human chromosome 9q22.1-q22.3 encompassing the loci for hereditary sensory neuropathy type I and multiple self-healing squamous epithelioma.Genomics. 1998 Jul 15;51(2):277-81. doi: 10.1006/geno.1998.5373.
• [14] Mutations in SPTLC1, encoding serine palmitoyltransferase, long chain base subunit-1, cause hereditary sensory neuropathy type I. Nat Genet. 2001 Mar;27(3):309-12. doi: 10.1038/85879.
• [15] 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.
• [16] SPTLC1 inhibits cell growth via modulating Akt/FOXO1 pathway in renal cell carcinoma cells.Biochem Biophys Res Commun. 2019 Nov 26;520(1):1-7. doi: 10.1016/j.bbrc.2019.09.073. Epub 2019 Sep 22.
• [17] Genome-wide association study in a Swedish population yields support for greater CNV and MHC involvement in schizophrenia compared with bipolar disorder.Mol Psychiatry. 2012 Sep;17(9):880-6. doi: 10.1038/mp.2012.73. Epub 2012 Jun 12.
• [18] Decreased SPTLC1 expression predicts worse outcomes in ccRCC patients.J Cell Biochem. 2020 Feb;121(2):1552-1562. doi: 10.1002/jcb.29390. Epub 2019 Sep 12.
• [19] A disease-causing mutation in the active site of serine palmitoyltransferase causes catalytic promiscuity.J Biol Chem. 2010 Jul 23;285(30):22846-52. doi: 10.1074/jbc.M110.122259. Epub 2010 May 26.
• [20] Novel functional association of serine palmitoyltransferase subunit 1-A peptide in sphingolipid metabolism with cytochrome P4501A1 transactivation and proliferative capacity of the human Glioma LN18 brain tumor cell line.Int J Environ Res Public Health. 2006 Sep;3(3):252-61. doi: 10.3390/ijerph2006030030.
• [21] Loss of Neurological Disease HSAN-I-Associated Gene SPTLC2 Impairs CD8(+) T Cell Responses to Infection by Inhibiting T Cell Metabolic Fitness.Immunity. 2019 May 21;50(5):1218-1231.e5. doi: 10.1016/j.immuni.2019.03.005. Epub 2019 Apr 2.
• [22] Systematic transcriptome-based comparison of cellular adaptive stress response activation networks in hepatic stem cell-derived progeny and primary human hepatocytes. Toxicol In Vitro. 2021 Jun;73:105107. doi: 10.1016/j.tiv.2021.105107. Epub 2021 Feb 3.
• [23] 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.
• [24] Proteomics-based identification of differentially abundant proteins from human keratinocytes exposed to arsenic trioxide. J Proteomics Bioinform. 2014 Jul;7(7):166-178.
• [25] Minimal peroxide exposure of neuronal cells induces multifaceted adaptive responses. PLoS One. 2010 Dec 17;5(12):e14352. doi: 10.1371/journal.pone.0014352.
• [26] Dihydroceramide accumulation mediates cytotoxic autophagy of cancer cells via autolysosome destabilization. Autophagy. 2016 Nov;12(11):2213-2229. doi: 10.1080/15548627.2016.1213927. Epub 2016 Sep 16.
• [27] Cannabidiol Displays Proteomic Similarities to Antipsychotics in Cuprizone-Exposed Human Oligodendrocytic Cell Line MO3.13. Front Mol Neurosci. 2021 May 28;14:673144. doi: 10.3389/fnmol.2021.673144. eCollection 2021.
• [28] 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.
• [29] Alternatives for the worse: Molecular insights into adverse effects of bisphenol a and substitutes during human adipocyte differentiation. Environ Int. 2021 Nov;156:106730. doi: 10.1016/j.envint.2021.106730. Epub 2021 Jun 27.
• [30] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [31] Toxicogenomics of kojic acid on gene expression profiling of a375 human malignant melanoma cells. Biol Pharm Bull. 2006 Apr;29(4):655-69.