Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTY265P6)

• DOT Name: Bis(monoacylglycero)phosphate synthase CLN5 (CLN5)
• Synonyms: BMP synthase CLN5; EC 2.3.1.-; Ceroid-lipofuscinosis neuronal protein 5; Protein CLN5; Palmitoyl protein thioesterase CLN5; EC 3.1.2.22; S-depalmitoylase CLN5
• Gene Name: CLN5
• Related Disease:
  Neuronal ceroid lipofuscinosis
  Neuronal ceroid lipofuscinosis 5
  Alzheimer disease
  Blindness
  Brain disease
  Cerebellar ataxia
  Lafora disease
  Neuronal ceroid lipofuscinosis 7
  Neuronal ceroid lipofuscinosis 8
  Neuronal ceroid lipofuscinosis 8 northern epilepsy variant
  CLN2 Batten disease
  Late infantile neuronal ceroid lipofuscinosis
  Adult neuronal ceroid lipofuscinosis
• UniProt ID: CLN5_HUMAN
• PDB ID: 6R99
• EC Number: 2.3.1.-; 3.1.2.22
• Pfam ID: PF15014
• Sequence:
  MAQEVDTAQGAEMRRGAGAARGRASWCWALALLWLAVVPGWSRVSGIPSRRHWPVPYKRF
  DFRPKPDPYCQAKYTFCPTGSPIPVMEGDDDIEVFRLQAPVWEFKYGDLLGHLKIMHDAI
  GFRSTLTGKNYTMEWYELFQLGNCTFPHLRPEMDAPFWCNQGAACFFEGIDDVHWKENGT
  LVQVATISGNMFNQMAKWVKQDNETGIYYETWNVKASPEKGAETWFDSYDCSKFVLRTFN
  KLAEFGAEFKNIETNYTRIFLYSGEPTYLGNETSVFGPTGNKTLGLAIKRFYYPFKPHLP
  TKEFLLSLLQIFDAVIVHKQFYLFYNFEYWFLPMKFPFIKITYEEIPLPIRNKTLSGL
• Function: [Bis(monoacylglycero)phosphate synthase CLN5, secreted form]: Catalyzes the synthesis of bis(monoacylglycero)phosphate (BMP) via transacylation of 2 molecules of lysophosphatidylglycerol (LPG). BMP also known as lysobisphosphatidic acid plays a key role in the formation of intraluminal vesicles and in maintaining intracellular cholesterol homeostasis. Can use only LPG as the exclusive lysophospholipid acyl donor for base exchange and displays BMP synthase activity towards various LPGs (LPG 14:0, LPG 16:0, LPG 18:0, LPG 18:1) with a higher preference for longer chain lengths. Plays a role in influencing the retrograde trafficking of lysosomal sorting receptors SORT1 and IGF2R from the endosomes to the trans-Golgi network by controlling the recruitment of retromer complex to the endosomal membrane. Regulates the localization and activation of RAB7A which is required to recruit the retromer complex to the endosomal membrane ; Exhibits palmitoyl protein thioesterase (S-depalmitoylation) activity in vitro and most likely plays a role in protein S-depalmitoylation.
• Tissue Specificity: Ubiquitous.
• KEGG Pathway: Lysosome (hsa04142)

Molecular Interaction Atlas (MIA) of This DOT

13 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Neuronal ceroid lipofuscinosis	DIS9A4K4	Definitive	Autosomal recessive	[1]
Neuronal ceroid lipofuscinosis 5	DISSKW1M	Definitive	Autosomal recessive	[1]
Alzheimer disease	DISF8S70	Strong	Genetic Variation	[2]
Blindness	DISTIM10	Strong	Biomarker	[3]
Brain disease	DIS6ZC3X	Strong	Biomarker	[4]
Cerebellar ataxia	DIS9IRAV	Strong	Genetic Variation	[5]
Lafora disease	DIS83JHH	Strong	Genetic Variation	[6]
Neuronal ceroid lipofuscinosis 7	DISVZUFT	Strong	Biomarker	[7]
Neuronal ceroid lipofuscinosis 8	DISGNC07	Strong	Biomarker	[8]
Neuronal ceroid lipofuscinosis 8 northern epilepsy variant	DISWF5BV	Strong	Biomarker	[8]
CLN2 Batten disease	DISZC5YB	moderate	Biomarker	[9]
Late infantile neuronal ceroid lipofuscinosis	DISI3RIL	moderate	Biomarker	[10]
Adult neuronal ceroid lipofuscinosis	DIS5UHAA	Limited	Biomarker	[11]

14 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 Bis(monoacylglycero)phosphate synthase CLN5 (CLN5).	[12]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Bis(monoacylglycero)phosphate synthase CLN5 (CLN5).	[13]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Bis(monoacylglycero)phosphate synthase CLN5 (CLN5).	[14]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Bis(monoacylglycero)phosphate synthase CLN5 (CLN5).	[15]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Bis(monoacylglycero)phosphate synthase CLN5 (CLN5).	[16]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Bis(monoacylglycero)phosphate synthase CLN5 (CLN5).	[17]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Bis(monoacylglycero)phosphate synthase CLN5 (CLN5).	[18]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Bis(monoacylglycero)phosphate synthase CLN5 (CLN5).	[19]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Bis(monoacylglycero)phosphate synthase CLN5 (CLN5).	[20]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Bis(monoacylglycero)phosphate synthase CLN5 (CLN5).	[21]
Torcetrapib	DMDHYM7	Discontinued in Phase 2	Torcetrapib increases the expression of Bis(monoacylglycero)phosphate synthase CLN5 (CLN5).	[22]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Bis(monoacylglycero)phosphate synthase CLN5 (CLN5).	[12]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Bis(monoacylglycero)phosphate synthase CLN5 (CLN5).	[23]
GALLICACID	DM6Y3A0	Investigative	GALLICACID decreases the expression of Bis(monoacylglycero)phosphate synthase CLN5 (CLN5).	[24]

References

• [1] 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.
• [2] An Alzheimer's Disease-Linked Loss-of-Function CLN5 Variant Impairs Cathepsin D Maturation, Consistent with a Retromer Trafficking Defect.Mol Cell Biol. 2018 Sep 28;38(20):e00011-18. doi: 10.1128/MCB.00011-18. Print 2018 Oct 15.
• [3] Retinal Degeneration In A Mouse Model Of CLN5 Disease Is Associated With Compromised Autophagy.Sci Rep. 2017 May 9;7(1):1597. doi: 10.1038/s41598-017-01716-1.
• [4] Lysosomal localization of the neuronal ceroid lipofuscinosis CLN5 protein.Hum Mol Genet. 2002 Apr 15;11(8):885-91. doi: 10.1093/hmg/11.8.885.
• [5] Adult-onset autosomal recessive ataxia associated with neuronal ceroid lipofuscinosis type 5 gene (CLN5) mutations.J Neurol. 2015 Jan;262(1):173-8. doi: 10.1007/s00415-014-7553-y. Epub 2014 Oct 31.
• [6] Advances in the genetics of progressive myoclonus epilepsy.Am J Med Genet. 2001 Summer;106(2):129-38. doi: 10.1002/ajmg.1575.
• [7] Loss of CLN7 results in depletion of soluble lysosomal proteins and impaired mTOR reactivation.Hum Mol Genet. 2018 May 15;27(10):1711-1722. doi: 10.1093/hmg/ddy076.
• [8] Studies of homogenous populations: CLN5 and CLN8.Adv Genet. 2001;45:123-40. doi: 10.1016/s0065-2660(01)45007-3.
• [9] Longitudinal InVivo Monitoring of the CNS Demonstrates the Efficacy of Gene Therapy in a Sheep Model of CLN5 Batten Disease.Mol Ther. 2018 Oct 3;26(10):2366-2378. doi: 10.1016/j.ymthe.2018.07.015. Epub 2018 Jul 17.
• [10] CLN5 mutations are frequent in juvenile and late-onset non-Finnish patients with NCL. Neurology. 2010 Feb 16;74(7):565-71. doi: 10.1212/WNL.0b013e3181cff70d.
• [11] A mouse model for Finnish variant late infantile neuronal ceroid lipofuscinosis, CLN5, reveals neuropathology associated with early aging.Hum Mol Genet. 2004 Dec 1;13(23):2893-906. doi: 10.1093/hmg/ddh312. Epub 2004 Sep 30.
• [12] 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.
• [13] 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.
• [14] 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.
• [15] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [16] 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.
• [17] 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.
• [18] 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.
• [19] 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.
• [20] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [21] 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.
• [22] Clarifying off-target effects for torcetrapib using network pharmacology and reverse docking approach. BMC Syst Biol. 2012 Dec 10;6:152.
• [23] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [24] Gene expression profile analysis of gallic acid-induced cell death process. Sci Rep. 2021 Aug 18;11(1):16743. doi: 10.1038/s41598-021-96174-1.