Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT1SLPGD)

• DOT Name: Pleckstrin homology domain-containing family M member 1 (PLEKHM1)
• Synonyms: PH domain-containing family M member 1; 162 kDa adapter protein; AP162
• Gene Name: PLEKHM1
• Related Disease:
  Pancreatic ductal carcinoma
  Retinitis pigmentosa
  Infantile malignant osteopetrosis
  Major depressive disorder
  Parkinson disease
  Autosomal recessive osteopetrosis 6
  Alopecia
  Epithelial ovarian cancer
  Osteopetrosis
  Osteopetrosis, autosomal dominant 3
  Ovarian neoplasm
  Ovarian serous adenocarcinoma
• UniProt ID: PKHM1_HUMAN
• PDB ID: 5DPR; 5DPS; 5DPT; 5DPW
• Pfam ID: PF13901 ; PF02759
• Sequence:
  MLSVVENGLDPQAAIPVIKKKLVGSVKALQKQYVSLDTVVTSEDGDANTMCSALEAVFIH
  GLHAKHIRAEAGGKRKKSAHQKPLPQPVFWPLLKAVTHKHIISELEHLTFVNTDVGRCRA
  WLRLALNDGLMECYLKLLLQEQARLHEYYQPTALLRDAEEGEFLLSFLQGLTSLSFELSY
  KSAILNEWTLTPLALSGLCPLSELDPLSTSGAELQRKESLDSISHSSGSEDIEVHHSGHK
  IRRNQKLTASSLSLDTASSSQLSCSLNSDSCLLQENGSKSPDHCEEPMSCDSDLGTANAE
  DSDRSLQEVLLEFSKAQVNSVPTNGLSQETEIPTPQASLSLHGLNTSTYLHCEAPAEPLP
  AQAASGTQDGVHVQEPRPQAPSPLDLQQPVESTSGQQPSSTVSETAREVGQGNGLQKAQA
  HDGAGLKLVVSSPTSPKNKSWISEDDFYRPSREQPLESASDHPIASYRGTPGSRPGLHRH
  FSQEPRKNCSLGALDQACVPSPGRRQAQAAPSQGHKSFRVVHRRQMGLSNPFRGLMKLGT
  VERRGAMGIWKELFCELSPLEFRLYLSNEEHTCVENCSLLRCESVGPAHSDGRFELVFSG
  KKLALRASSQDEAEDWLDRVREALQKVRPQQEDEWVNVQYPDQPEEPPEAPQGCLSPSDL
  LSEPAALQGTQFDWSSAQVPEPDAIKESLLYLYMDRTWMPYIFSLSLEALKCFRIRNNEK
  MLSDSHGVETIRDILPDTSLGGPSFFKIITAKAVLKLQAGNAEEAALWRDLVRKVLASYL
  ETAEEAVTLGGSLDENCQEVLKFATRENGFLLQYLVAIPMEKGLDSQGCFCAGCSRQIGF
  SFVRPKLCAFSGLYYCDICHQDDASVIPARIIHNWDLTKRPICRQALKFLTQIRAQPLIN
  LQMVNASLYEHVERMHLIGRRREQLKLLGDYLGLCRSGALKELSKRLNHRNYLLESPHRF
  SVADLQQIADGVYEGFLKALIEFASQHVYHCDLCTQRGFICQICQHHDIIFPFEFDTTVR
  CAECKTVFHQSCQAVVKKGCPRCARRRKYQEQNIFA
• Function: Acts as a multivalent adapter protein that regulates Rab7-dependent and HOPS complex-dependent fusion events in the endolysosomal system and couples autophagic and the endocytic trafficking pathways. Acts as a dual effector of RAB7A and ARL8B that simultaneously binds these GTPases, bringing about clustering and fusion of late endosomes and lysosomes. Required for late stages of endolysosomal maturation, facilitating both endocytosis-mediated degradation of growth factor receptors and autophagosome clearance. Interaction with Arl8b is a crucial factor in the terminal maturation of autophagosomes and to mediate autophagosome-lysosome fusion. Positively regulates lysosome peripheral distribution and ruffled border formation in osteoclasts. May be involved in negative regulation of endocytic transport from early endosome to late endosome/lysosome implicating its association with Rab7. May have a role in sialyl-lex-mediated transduction of apoptotic signals. Involved in bone resorption; (Microbial infection) In case of infection contributes to Salmonella typhimurium pathogenesis by supporting the integrity of the Salmonella-containing vacuole (SCV) probably in concert with the HOPS complex and Rab7.
• Tissue Specificity: Expressed in placenta, liver, prostate, thymus, spleen, ovary, colon, colon carcinoma and peripheral blood lymphocytes (PBL). Weakly expressed in brain, lung, kidney, and testis. No expression in heart, skeletal muscle, pancreas and small intestine. Predominantly expressed in the breast carcinoma cell line MCF-7.
• KEGG Pathway:
  Autophagy - animal (hsa04140)
  Salmonella infection (hsa05132)

Molecular Interaction Atlas (MIA) of This DOT

12 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Pancreatic ductal carcinoma	DIS26F9Q	Definitive	Altered Expression	[1]
Retinitis pigmentosa	DISCGPY8	Definitive	Biomarker	[1]
Infantile malignant osteopetrosis	DIS8C3LZ	Strong	Biomarker	[2]
Major depressive disorder	DIS4CL3X	Strong	Genetic Variation	[3]
Parkinson disease	DISQVHKL	Strong	Genetic Variation	[4]
Autosomal recessive osteopetrosis 6	DIS5LWCT	Moderate	Autosomal recessive	[5]
Alopecia	DIS37HU4	Limited	Genetic Variation	[6]
Epithelial ovarian cancer	DIS56MH2	Limited	Biomarker	[7]
Osteopetrosis	DIS7GHNM	Limited	Biomarker	[8]
Osteopetrosis, autosomal dominant 3	DISRBVO7	Limited	Autosomal dominant	[5]
Ovarian neoplasm	DISEAFTY	Limited	Genetic Variation	[9]
Ovarian serous adenocarcinoma	DISSU72Z	Limited	Genetic Variation	[9]

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 Pleckstrin homology domain-containing family M member 1 (PLEKHM1).	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Pleckstrin homology domain-containing family M member 1 (PLEKHM1).	[11]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Pleckstrin homology domain-containing family M member 1 (PLEKHM1).	[12]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Pleckstrin homology domain-containing family M member 1 (PLEKHM1).	[13]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Pleckstrin homology domain-containing family M member 1 (PLEKHM1).	[14]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Pleckstrin homology domain-containing family M member 1 (PLEKHM1).	[15]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of Pleckstrin homology domain-containing family M member 1 (PLEKHM1).	[16]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Pleckstrin homology domain-containing family M member 1 (PLEKHM1).	[17]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Pleckstrin homology domain-containing family M member 1 (PLEKHM1).	[18]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Pleckstrin homology domain-containing family M member 1 (PLEKHM1).	[19]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of Pleckstrin homology domain-containing family M member 1 (PLEKHM1).	[20]

References

• [1] Diverse mechanisms of autophagy dysregulation and their therapeutic implications: does the shoe fit?.Autophagy. 2019 Feb;15(2):368-371. doi: 10.1080/15548627.2018.1509609. Epub 2018 Sep 13.
• [2] Novel mutations of TCIRG1 cause a malignant and mild phenotype of autosomal recessive osteopetrosis (ARO) in four Chinese families.Acta Pharmacol Sin. 2017 Nov;38(11):1456-1465. doi: 10.1038/aps.2017.108. Epub 2017 Aug 17.
• [3] Association of the Polygenic Scores for Personality Traits and Response to Selective Serotonin Reuptake Inhibitors in Patients with Major Depressive Disorder.Front Psychiatry. 2018 Mar 6;9:65. doi: 10.3389/fpsyt.2018.00065. eCollection 2018.
• [4] Comprehensive research synopsis and systematic meta-analyses in Parkinson's disease genetics: The PDGene database.PLoS Genet. 2012;8(3):e1002548. doi: 10.1371/journal.pgen.1002548. Epub 2012 Mar 15.
• [5] 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.
• [6] Genetic prediction of male pattern baldness.PLoS Genet. 2017 Feb 14;13(2):e1006594. doi: 10.1371/journal.pgen.1006594. eCollection 2017 Feb.
• [7] Identification and molecular characterization of a new ovarian cancer susceptibility locus at 17q21.31.Nat Commun. 2013;4:1627. doi: 10.1038/ncomms2613.
• [8] Characterization of a Relatively Malignant Form of Osteopetrosis Caused by a Novel Mutation in the PLEKHM1 Gene.J Bone Miner Res. 2016 Nov;31(11):1979-1987. doi: 10.1002/jbmr.2885. Epub 2016 Jul 13.
• [9] Identification of 12 new susceptibility loci for different histotypes of epithelial ovarian cancer.Nat Genet. 2017 May;49(5):680-691. doi: 10.1038/ng.3826. Epub 2017 Mar 27.
• [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] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [12] 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.
• [13] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [14] 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.
• [15] 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.
• [16] 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.
• [17] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [18] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [19] 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.
• [20] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.