Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTWH1ULQ)

• DOT Name: Protein SERAC1 (SERAC1)
• Synonyms: Serine active site-containing protein 1
• Gene Name: SERAC1
• Related Disease:
  3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome
  Leigh syndrome
  3-methylglutaconic aciduria type 3
  3-methylglutaconic aciduria type 5
  Acute liver failure
  Dystonia
  Hypoglycemia
  Mitochondrial disease
  Narcolepsy
  Complex hereditary spastic paraplegia
  Paroxysmal dystonia
  3-methylglutaconic aciduria
  Intellectual disability
• UniProt ID: SRAC1_HUMAN
• Sequence:
  MSLAAYCVICCRRIGTSTSPPKSGTHWRDIRNIIKFTGSLILGGSLFLTYEVLALKKAVT
  LDTQVVEREKMKSYIYVHTVSLDKGENHGIAWQARKELHKAVRKVLATSAKILRNPFADP
  FSTVDIEDHECAVWLLLRKSKSDDKTTRLEAVREMSETHHWHDYQYRIIAQACDPKTLIG
  LARSEESDLRFFLLPPPLPSLKEDSSTEEELRQLLASLPQTELDECIQYFTSLALSESSQ
  SLAAQKGGLWCFGGNGLPYAESFGEVPSATVEMFCLEAIVKHSEISTHCDKIEANGGLQL
  LQRLYRLHKDCPKVQRNIMRVIGNMALNEHLHSSIVRSGWVSIMAEAMKSPHIMESSHAA
  RILANLDRETVQEKYQDGVYVLHPQYRTSQPIKADVLFIHGLMGAAFKTWRQQDSEQAVI
  EKPMEDEDRYTTCWPKTWLAKDCPALRIISVEYDTSLSDWRARCPMERKSIAFRSNELLR
  KLRAAGVGDRPVVWISHSMGGLLVKKMLLEASTKPEMSTVINNTRGIIFYSVPHHGSRLA
  EYSVNIRYLLFPSLEVKELSKDSPALKTLQDDFLEFAKDKNFQVLNFVETLPTYIGSMIK
  LHVVPVESADLGIGDLIPVDVNHLNICKPKKKDAFLYQRTLQFIREALAKDLEN
• Function: Plays an important role in the phosphatidylglycerol remodeling that is essential for both mitochondrial function and intracellular cholesterol trafficking. May catalyze the remodeling of phosphatidylglycerol and be involved in the transacylation-acylation reaction to produce phosphatidylglycerol-36:1. May be involved in bis(monoacylglycerol)phosphate biosynthetic pathway.
• Tissue Specificity: Widely expressed, with predominant expression in fetal skeletal muscle and adult brain. In the brain, highest levels are found in the frontal and occipital cortices, cerebellum and hippocampus.

Molecular Interaction Atlas (MIA) of This DOT

13 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome	DISKAAPW	Definitive	Autosomal recessive	[1]
Leigh syndrome	DISWQU45	Definitive	Autosomal recessive	[2]
3-methylglutaconic aciduria type 3	DISDQMDY	Strong	Biomarker	[3]
3-methylglutaconic aciduria type 5	DISEP4OP	Strong	Biomarker	[3]
Acute liver failure	DIS5EZKX	Strong	Genetic Variation	[4]
Dystonia	DISJLFGW	Strong	Genetic Variation	[1]
Hypoglycemia	DISRCKR7	Strong	Biomarker	[5]
Mitochondrial disease	DISKAHA3	Strong	Biomarker	[6]
Narcolepsy	DISLCNLI	Strong	Genetic Variation	[7]
Complex hereditary spastic paraplegia	DIS9KXQY	Disputed	Genetic Variation	[8]
Paroxysmal dystonia	DISV0MSQ	Disputed	Biomarker	[9]
3-methylglutaconic aciduria	DIS8G1WP	Limited	Genetic Variation	[10]
Intellectual disability	DISMBNXP	Limited	Genetic Variation	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of Protein SERAC1 (SERAC1).	[11]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Protein SERAC1 (SERAC1).	[12]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Protein SERAC1 (SERAC1).	[13]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Protein SERAC1 (SERAC1).	[14]
Quercetin	DM3NC4M	Approved	Quercetin affects the expression of Protein SERAC1 (SERAC1).	[16]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide increases the expression of Protein SERAC1 (SERAC1).	[17]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of Protein SERAC1 (SERAC1).	[18]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Protein SERAC1 (SERAC1).	[19]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Protein SERAC1 (SERAC1).	[20]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Protein SERAC1 (SERAC1).	[21]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Protein SERAC1 (SERAC1).	[22]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Protein SERAC1 (SERAC1).	[15]

References

• [1] Novel mutations in SERAC1 gene in two Indian patients presenting with dystonia and intellectual disability. Eur J Med Genet. 2018 Feb;61(2):100-103. doi: 10.1016/j.ejmg.2017.07.013. Epub 2017 Aug 1.
• [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] Inborn errors of metabolism with 3-methylglutaconic aciduria as discriminative feature: proper classification and nomenclature.J Inherit Metab Dis. 2013 Nov;36(6):923-8. doi: 10.1007/s10545-012-9580-0. Epub 2013 Jan 8.
• [4] Individual exome analysis in diagnosis and management of paediatric liver failure of indeterminate aetiology.J Hepatol. 2014 Nov;61(5):1056-63. doi: 10.1016/j.jhep.2014.06.038. Epub 2014 Jul 10.
• [5] Advantages and pitfalls of an extended gene panel for investigating complex neurometabolic phenotypes.Brain. 2016 Nov 1;139(11):2844-2854. doi: 10.1093/brain/aww221.
• [6] Congenital cochlear deafness in mitochondrial diseases related to RRM2B and SERAC1 gene defects. A study of the mitochondrial patients of the CMHI hospital in Warsaw, Poland.Int J Pediatr Otorhinolaryngol. 2019 Jun;121:143-149. doi: 10.1016/j.ijporl.2019.03.015. Epub 2019 Mar 16.
• [7] Genome-wide association database developed in the Japanese Integrated Database Project.J Hum Genet. 2009 Sep;54(9):543-6. doi: 10.1038/jhg.2009.68. Epub 2009 Jul 24.
• [8] SERAC1 deficiency causes complicated HSP: evidence from a novel splice mutation in a large family.J Med Genet. 2018 Jan;55(1):39-47. doi: 10.1136/jmedgenet-2017-104622. Epub 2017 Sep 15.
• [9] Mutations in the phospholipid remodeling gene SERAC1 impair mitochondrial function and intracellular cholesterol trafficking and cause dystonia and deafness. Nat Genet. 2012 Jun 10;44(7):797-802. doi: 10.1038/ng.2325.
• [10] Identification of a novel splice site mutation in the SERAC1 gene responsible for the MEGDHEL syndrome.Mol Genet Genomic Med. 2019 Aug;7(8):e815. doi: 10.1002/mgg3.815. Epub 2019 Jun 28.
• [11] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [12] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [13] 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.
• [14] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [15] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [16] 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.
• [17] Oxidative stress modulates theophylline effects on steroid responsiveness. Biochem Biophys Res Commun. 2008 Dec 19;377(3):797-802.
• [18] Folic acid supplementation dysregulates gene expression in lymphoblastoid cells--implications in nutrition. Biochem Biophys Res Commun. 2011 Sep 9;412(4):688-92. doi: 10.1016/j.bbrc.2011.08.027. Epub 2011 Aug 16.
• [19] Benzo[a]pyrene-induced changes in microRNA-mRNA networks. Chem Res Toxicol. 2012 Apr 16;25(4):838-49.
• [20] 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.
• [21] 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.
• [22] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.