Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT1YA9CS)

• DOT Name: Pleckstrin homology domain-containing family M member 3 (PLEKHM3)
• Synonyms: PH domain-containing family M member 3; Differentiation associated protein
• Gene Name: PLEKHM3
• Related Disease:
  Charcot marie tooth disease
  Chronic obstructive pulmonary disease
• UniProt ID: PKHM3_HUMAN
• Pfam ID: PF00169 ; PF13901
• Sequence:
  MEALEVDDISPALEVTEEFFSTLDSNLEKAVQQAEVYGIQEVPELVGHEVLSNITDNGAM
  RNVTSLGKGGMIWDHCKSRLLETKAQNVFPAKEQFMVQRGTTPDNLSWMEQKEASTFNFF
  NICQRRRDRPRSVNDLLDETSTFKPGHARSRSDITQVDWRVVLKTTPLQQQQQQQPLLQG
  PHVTRPSFLLPSPNKIEDAQGNTEHKQTFPNILKKGYLEIRKDHDSYWQSCYAELSPYNL
  YFYSLDSSGNQNLYATYQLSHFQSISVLGNLEARMVDTVLYDNTQLQLKAESPWEALDWG
  QKLWEVVHAAVPGYMGRQNELTISPGLGHHDDYTQNHSFQKKTSGLLPPSPVLDSSKQYQ
  NILKSGTLYRLTVQNNWKAFTFVLSRAYLMAFQPGKLDEDPLLSYNVDVCLAVQMDNLDG
  CDSCFQVIFPQDVLRLRAETRQRAQEWMEALKIAANVARSSEQNLQVTLRNKPKDQMGGH
  ELRKNKRQSVTTSFLSILTTLSLERGLTAQSFKCAGCQRSIGLSNGKAKVCNYSGWYYCS
  SCHVDDSFLIPARIVHNWDTSKYKVSKQAKEFLEYVYEEPLIDIQQENAMLYHHAEPLAA
  VLRLRQRLKSLRAYLFSCRAAVAEDLRRRIFPREYLLQQIHLYSLADLQQVIEGKLAPFL
  GKVIKFATSHVYSCSLCSQKGFICEICNNGEILYPFEDISTSRCESCGAVFHSECKEKSV
  PCPRCVRRELQKKQKSFWQRLNMDESLEEACTMFELSYQNT
• Function: Involved in skeletal muscle differentiation. May act as a scaffold protein for AKT1 during muscle differentiation.

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Charcot marie tooth disease	DIS3BT2L	Strong	Biomarker	[1]
Chronic obstructive pulmonary disease	DISQCIRF	moderate	Biomarker	[2]

10 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 Pleckstrin homology domain-containing family M member 3 (PLEKHM3).	[3]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Pleckstrin homology domain-containing family M member 3 (PLEKHM3).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Pleckstrin homology domain-containing family M member 3 (PLEKHM3).	[5]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Pleckstrin homology domain-containing family M member 3 (PLEKHM3).	[6]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Pleckstrin homology domain-containing family M member 3 (PLEKHM3).	[7]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Pleckstrin homology domain-containing family M member 3 (PLEKHM3).	[8]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Pleckstrin homology domain-containing family M member 3 (PLEKHM3).	[10]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Pleckstrin homology domain-containing family M member 3 (PLEKHM3).	[11]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Pleckstrin homology domain-containing family M member 3 (PLEKHM3).	[12]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Pleckstrin homology domain-containing family M member 3 (PLEKHM3).	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Pleckstrin homology domain-containing family M member 3 (PLEKHM3).	[9]

References

• [1] Calcium Deregulation and Mitochondrial Bioenergetics in GDAP1-Related CMT Disease.Int J Mol Sci. 2019 Jan 18;20(2):403. doi: 10.3390/ijms20020403.
• [2] A Genome-Wide Linkage Study for Chronic Obstructive Pulmonary Disease in a Dutch Genetic Isolate Identifies Novel Rare Candidate Variants.Front Genet. 2018 Apr 19;9:133. doi: 10.3389/fgene.2018.00133. eCollection 2018.
• [3] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [4] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [5] 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.
• [6] 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.
• [7] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [8] 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.
• [9] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [10] 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.
• [11] Comparison of transcriptome expression alterations by chronic exposure to low-dose bisphenol A in different subtypes of breast cancer cells. Toxicol Appl Pharmacol. 2019 Dec 15;385:114814. doi: 10.1016/j.taap.2019.114814. Epub 2019 Nov 9.
• [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] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.