Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTDP4F02)

• DOT Name: Lysophosphatidylserine lipase ABHD12 (ABHD12)
• Synonyms: EC 3.1.-.-; 2-arachidonoylglycerol hydrolase ABHD12; Abhydrolase domain-containing protein 12; hABHD12; Monoacylglycerol lipase ABHD12; EC 3.1.1.23; Oxidized phosphatidylserine lipase ABHD12; EC 3.1.-.-
• Gene Name: ABHD12
• Related Disease:
  Inherited retinal dystrophy
  Nervous system disease
  PHARC syndrome
  Blindness
  Cataract
  Deafness
  Demyelinating polyneuropathy
  Hereditary ataxia
  Pathologic nystagmus
  Retinitis pigmentosa
  Retinopathy
  Sensorineural hearing loss disorder
  Usher syndrome
  Usher syndrome type 3
  Polyneuropathy
• UniProt ID: ABD12_HUMAN
• EC Number: 3.1.-.-; 3.1.1.23
• Pfam ID: PF00561
• Sequence:
  MRKRTEPVALEHERCAAAGSSSSGSAAAALDADCRLKQNLRLTGPAAAEPRCAADAGMKR
  ALGRRKGVWLRLRKILFCVLGLYIAIPFLIKLCPGIQAKLIFLNFVRVPYFIDLKKPQDQ
  GLNHTCNYYLQPEEDVTIGVWHTVPAVWWKNAQGKDQMWYEDALASSHPIILYLHGNAGT
  RGGDHRVELYKVLSSLGYHVVTFDYRGWGDSVGTPSERGMTYDALHVFDWIKARSGDNPV
  YIWGHSLGTGVATNLVRRLCERETPPDALILESPFTNIREEAKSHPFSVIYRYFPGFDWF
  FLDPITSSGIKFANDENVKHISCPLLILHAEDDPVVPFQLGRKLYSIAAPARSFRDFKVQ
  FVPFHSDLGYRHKYIYKSPELPRILREFLGKSEPEHQH
• Function: Lysophosphatidylserine (LPS) lipase that mediates the hydrolysis of lysophosphatidylserine, a class of signaling lipids that regulates immunological and neurological processes. Represents a major lysophosphatidylserine lipase in the brain, thereby playing a key role in the central nervous system. Also able to hydrolyze oxidized phosphatidylserine; oxidized phosphatidylserine is produced in response to severe inflammatory stress and constitutes a proapoptotic 'eat me' signal. Also has monoacylglycerol (MAG) lipase activity: hydrolyzes 2-arachidonoylglycerol (2-AG), thereby acting as a regulator of endocannabinoid signaling pathways. Has a strong preference for very-long-chain lipid substrates; substrate specificity is likely due to improved catalysis and not improved substrate binding.
• Reactome Pathway: Arachidonate production from DAG (R-HSA-426048)

Molecular Interaction Atlas (MIA) of This DOT

15 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Inherited retinal dystrophy	DISGGL77	Definitive	CausalMutation	[1]
Nervous system disease	DISJ7GGT	Definitive	Genetic Variation	[2]
PHARC syndrome	DISU4IBC	Definitive	Autosomal recessive	[3]
Blindness	DISTIM10	Strong	Genetic Variation	[4]
Cataract	DISUD7SL	Strong	Genetic Variation	[5]
Deafness	DISKCLH4	Strong	Biomarker	[6]
Demyelinating polyneuropathy	DIS7IO4W	Strong	Biomarker	[5]
Hereditary ataxia	DIS6JNI3	Strong	Biomarker	[7]
Pathologic nystagmus	DIS1QSPO	Strong	CausalMutation	[5]
Retinitis pigmentosa	DISCGPY8	Strong	Biomarker	[6]
Retinopathy	DISB4B0F	Strong	Biomarker	[5]
Sensorineural hearing loss disorder	DISJV45Z	Strong	CausalMutation	[5]
Usher syndrome	DIS9YIS7	Strong	Genetic Variation	[8]
Usher syndrome type 3	DISRAL84	Strong	Genetic Variation	[9]
Polyneuropathy	DISB9G3W	moderate	Biomarker	[5]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Lysophosphatidylserine lipase ABHD12 (ABHD12).	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Lysophosphatidylserine lipase ABHD12 (ABHD12).	[11]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Lysophosphatidylserine lipase ABHD12 (ABHD12).	[12]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Lysophosphatidylserine lipase ABHD12 (ABHD12).	[13]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Lysophosphatidylserine lipase ABHD12 (ABHD12).	[14]
Cannabidiol	DM0659E	Approved	Cannabidiol increases the expression of Lysophosphatidylserine lipase ABHD12 (ABHD12).	[15]
Orlistat	DMRJSP8	Approved	Orlistat decreases the activity of Lysophosphatidylserine lipase ABHD12 (ABHD12).	[16]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Lysophosphatidylserine lipase ABHD12 (ABHD12).	[17]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Lysophosphatidylserine lipase ABHD12 (ABHD12).	[18]

References

• [1] Targeted next-generation sequencing identifies a homozygous nonsense mutation in ABHD12, the gene underlying PHARC, in a family clinically diagnosed with Usher syndrome type 3.Orphanet J Rare Dis. 2012 Sep 2;7:59. doi: 10.1186/1750-1172-7-59.
• [2] Selective blockade of the lyso-PS lipase ABHD12 stimulates immune responses in vivo.Nat Chem Biol. 2018 Dec;14(12):1099-1108. doi: 10.1038/s41589-018-0155-8. Epub 2018 Nov 12.
• [3] 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.
• [4] Novel ABHD12 mutations in PHARC patients: the differential diagnosis of deaf-blindness.Ann Otol Rhinol Laryngol. 2015 May;124 Suppl 1:77S-83S. doi: 10.1177/0003489415574513. Epub 2015 Mar 5.
• [5] Phenotypical features of two patients diagnosed with PHARC syndrome and carriers of a new homozygous mutation in the ABHD12 gene.J Neurol Sci. 2018 Apr 15;387:134-138. doi: 10.1016/j.jns.2018.02.021. Epub 2018 Feb 7.
• [6] Exome sequencing extends the phenotypic spectrum for ABHD12 mutations: from syndromic to nonsyndromic retinal degeneration.Ophthalmology. 2014 Aug;121(8):1620-7. doi: 10.1016/j.ophtha.2014.02.008. Epub 2014 Mar 31.
• [7] 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.
• [8] Comprehensive Molecular Screening in Chinese Usher Syndrome Patients.Invest Ophthalmol Vis Sci. 2018 Mar 1;59(3):1229-1237. doi: 10.1167/iovs.17-23312.
• [9] A novel ABHD12 nonsense variant in Usher syndrome type 3 family with genotype-phenotype spectrum review.Gene. 2019 Jul 1;704:113-120. doi: 10.1016/j.gene.2019.04.008. Epub 2019 Apr 8.
• [10] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [11] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [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] 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.
• [14] 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.
• [15] Cannabidiol Activates Neuronal Precursor Genes in Human Gingival Mesenchymal Stromal Cells. J Cell Biochem. 2017 Jun;118(6):1531-1546. doi: 10.1002/jcb.25815. Epub 2016 Dec 29.
• [16] Selectivity of inhibitors of endocannabinoid biosynthesis evaluated by activity-based protein profiling. Bioorg Med Chem Lett. 2008 Nov 15;18(22):5838-41.
• [17] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [18] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.