Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTP0FHOV)

• DOT Name: O-phosphoseryl-tRNA(Sec) selenium transferase (SEPSECS)
• Synonyms: EC 2.9.1.2; Liver-pancreas antigen; LP; SLA-p35; SLA/LP autoantigen; Selenocysteine synthase; Sec synthase; Selenocysteinyl-tRNA(Sec) synthase; Sep-tRNA:Sec-tRNA synthase; SepSecS; Soluble liver antigen; SLA; UGA suppressor tRNA-associated protein; tRNA(Ser/Sec)-associated antigenic protein
• Gene Name: SEPSECS
• Related Disease:
  Pontocerebellar hypoplasia type 2D
  Autoimmune hepatitis
  Isolated congenital microcephaly
  PEHO syndrome
  PEHO-like syndrome
  Neurodevelopmental disorder
  Obsolete progressive cerebello-cerebral atrophy
  Pontocerebellar hypoplasia type 2
  Nervous system disease
• UniProt ID: SPCS_HUMAN
• PDB ID: 3HL2; 4ZDL; 4ZDO; 4ZDP; 7L1T; 7MDL; 8G9Z
• EC Number: 2.9.1.2
• Pfam ID: PF05889
• Sequence:
  MNRESFAAGERLVSPAYVRQGCEARRSHEHLIRLLLEKGKCPENGWDESTLELFLHELAI
  MDSNNFLGNCGVGEREGRVASALVARRHYRFIHGIGRSGDISAVQPKAAGSSLLNKITNS
  LVLDIIKLAGVHTVANCFVVPMATGMSLTLCFLTLRHKRPKAKYIIWPRIDQKSCFKSMI
  TAGFEPVVIENVLEGDELRTDLKAVEAKVQELGPDCILCIHSTTSCFAPRVPDRLEELAV
  ICANYDIPHIVNNAYGVQSSKCMHLIQQGARVGRIDAFVQSLDKNFMVPVGGAIIAGFND
  SFIQEISKMYPGRASASPSLDVLITLLSLGSNGYKKLLKERKEMFSYLSNQIKKLSEAYN
  ERLLHTPHNPISLAMTLKTLDEHRDKAVTQLGSMLFTRQVSGARVVPLGSMQTVSGYTFR
  GFMSHTNNYPCAYLNAASAIGMKMQDVDLFIKRLDRCLKAVRKERSKESDDNYDKTEDVD
  IEEMALKLDNVLLDTYQDASS
• Function: Converts O-phosphoseryl-tRNA(Sec) to selenocysteinyl-tRNA(Sec) required for selenoprotein biosynthesis.
• Tissue Specificity: Primarily expressed in liver, pancreas, kidney and lung. Overexpressed in PHA-stimulated T-cells.
• KEGG Pathway:
  Selenocompound metabolism (hsa00450)
  Aminoacyl-tR. biosynthesis (hsa00970)
  Metabolic pathways (hsa01100)
• Reactome Pathway: Selenocysteine synthesis (R-HSA-2408557)

Molecular Interaction Atlas (MIA) of This DOT

9 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Pontocerebellar hypoplasia type 2D	DISD33KW	Definitive	Autosomal recessive	[1]
Autoimmune hepatitis	DISOX03Q	Strong	Biomarker	[2]
Isolated congenital microcephaly	DISUXHZ6	Strong	Genetic Variation	[1]
PEHO syndrome	DISPO5IP	Strong	Genetic Variation	[3]
PEHO-like syndrome	DIS1SRCH	Strong	Genetic Variation	[3]
Neurodevelopmental disorder	DIS372XH	moderate	Genetic Variation	[4]
Obsolete progressive cerebello-cerebral atrophy	DISPEWML	Supportive	Autosomal recessive	[5]
Pontocerebellar hypoplasia type 2	DISXV76G	Supportive	Autosomal recessive	[5]
Nervous system disease	DISJ7GGT	Limited	Genetic Variation	[6]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic trioxide	DM61TA4	Approved	O-phosphoseryl-tRNA(Sec) selenium transferase (SEPSECS) decreases the response to substance of Arsenic trioxide.	[19]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of O-phosphoseryl-tRNA(Sec) selenium transferase (SEPSECS).	[7]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of O-phosphoseryl-tRNA(Sec) selenium transferase (SEPSECS).	[8]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of O-phosphoseryl-tRNA(Sec) selenium transferase (SEPSECS).	[9]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of O-phosphoseryl-tRNA(Sec) selenium transferase (SEPSECS).	[10]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of O-phosphoseryl-tRNA(Sec) selenium transferase (SEPSECS).	[11]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of O-phosphoseryl-tRNA(Sec) selenium transferase (SEPSECS).	[12]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of O-phosphoseryl-tRNA(Sec) selenium transferase (SEPSECS).	[13]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of O-phosphoseryl-tRNA(Sec) selenium transferase (SEPSECS).	[14]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of O-phosphoseryl-tRNA(Sec) selenium transferase (SEPSECS).	[15]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of O-phosphoseryl-tRNA(Sec) selenium transferase (SEPSECS).	[16]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of O-phosphoseryl-tRNA(Sec) selenium transferase (SEPSECS).	[17]
Resorcinol	DMM37C0	Investigative	Resorcinol decreases the expression of O-phosphoseryl-tRNA(Sec) selenium transferase (SEPSECS).	[18]

References

• [1] A SEPSECS mutation in a 23-year-old woman with microcephaly and progressive cerebellar ataxia. J Inherit Metab Dis. 2018 Sep;41(5):897-898. doi: 10.1007/s10545-018-0151-x. Epub 2018 Feb 20.
• [2] Permanent immunosuppression in SLA/LP-positive autoimmune hepatitis is required although overall response and survival are similar.Liver Int. 2020 Feb;40(2):368-376. doi: 10.1111/liv.14280. Epub 2019 Nov 1.
• [3] Progressive cerebello-cerebral atrophy and progressive encephalopathy with edema, hypsarrhythmia and optic atrophy may be allelic syndromes.Eur J Paediatr Neurol. 2018 Nov;22(6):1133-1138. doi: 10.1016/j.ejpn.2018.07.003. Epub 2018 Jul 26.
• [4] Why 21? The significance of selenoproteins for human health revealed by inborn errors of metabolism.FASEB J. 2016 Nov;30(11):3669-3681. doi: 10.1096/fj.201600424. Epub 2016 Jul 29.
• [5] Mutations disrupting selenocysteine formation cause progressive cerebello-cerebral atrophy. Am J Hum Genet. 2010 Oct 8;87(4):538-44. doi: 10.1016/j.ajhg.2010.09.007.
• [6] Selenium homeostasis and antioxidant selenoproteins in brain: implications for disorders in the central nervous system.Arch Biochem Biophys. 2013 Aug 15;536(2):152-7. doi: 10.1016/j.abb.2013.02.021. Epub 2013 Mar 13.
• [7] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [8] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [9] 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.
• [10] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [11] 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.
• [12] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [13] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [14] 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.
• [15] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [16] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [17] 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.
• [18] A transcriptomics-based in vitro assay for predicting chemical genotoxicity in vivo. Carcinogenesis. 2012 Jul;33(7):1421-9.
• [19] Functional Profiling Identifies Determinants of Arsenic Trioxide Cellular Toxicity. Toxicol Sci. 2019 May 1;169(1):108-121. doi: 10.1093/toxsci/kfz024.