Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT6Q5M0C)

• DOT Name: Serine/threonine-protein phosphatase PGAM5, mitochondrial (PGAM5)
• Synonyms: EC 3.1.3.16; Bcl-XL-binding protein v68; Phosphoglycerate mutase family member 5
• Gene Name: PGAM5
• Related Disease:
  Neoplasm
  Autoimmune hepatitis
  Autosomal dominant optic atrophy, classic form
  Bronchiolitis
  Chronic obstructive pulmonary disease
  Colorectal carcinoma
  Hepatitis
  Hepatitis A virus infection
  Non-small-cell lung cancer
  Obesity
  Pneumonia
  Pneumonitis
  Pulmonary fibrosis
  Advanced cancer
  Autoimmune disease
  Hepatocellular carcinoma
  Nervous system inflammation
• UniProt ID: PGAM5_HUMAN
• PDB ID: 3MXO; 3O0T; 5MUF; 6CNI; 6CNL; 7QAL; 7QAM; 7QAO; 7QAP
• EC Number: 3.1.3.16
• Pfam ID: PF00300
• Sequence:
  MAFRQALQLAACGLAGGSAAVLFSAVAVGKPRAGGDAEPRPAEPPAWAGGARPGPGVWDP
  NWDRREPLSLINVRKRNVESGEEELASKLDHYKAKATRHIFLIRHSQYHVDGSLEKDRTL
  TPLGREQAELTGLRLASLGLKFNKIVHSSMTRAIETTDIISRHLPGVCKVSTDLLREGAP
  IEPDPPVSHWKPEAVQYYEDGARIEAAFRNYIHRADARQEEDSYEIFICHANVIRYIVCR
  ALQFPPEGWLRLSLNNGSITHLVIRPNGRVALRTLGDTGFMPPDKITRS
• Function: Mitochondrial serine/threonine phosphatase that dephosphorylates various substrates and thus plays a role in different biological processes including cellular senescence or mitophagy. Modulates cellular senescence by regulating mitochondrial dynamics. Mechanistically, participates in mitochondrial fission through dephosphorylating DNM1L/DRP1. Additionally, dephosphorylates MFN2 in a stress-sensitive manner and consequently protects it from ubiquitination and degradation to promote mitochondrial network formation. Regulates mitophagy independent of PARKIN by interacting with and dephosphorylating FUNDC1, which interacts with LC3. Regulates anti-oxidative response by forming a tertiary complex with KEAP1 and NRF2. Regulates necroptosis by acting as a RIPK3 target and recruiting the RIPK1-RIPK3-MLKL necrosis 'attack' complex to mitochondria.
• KEGG Pathway:
  Mitophagy - animal (hsa04137)
  Necroptosis (hsa04217)
  TNF sig.ling pathway (hsa04668)

Molecular Interaction Atlas (MIA) of This DOT

17 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Neoplasm	DISZKGEW	Definitive	Biomarker	[1]
Autoimmune hepatitis	DISOX03Q	Strong	Altered Expression	[2]
Autosomal dominant optic atrophy, classic form	DISXUAV9	Strong	Altered Expression	[3]
Bronchiolitis	DISEE9BG	Strong	Biomarker	[4]
Chronic obstructive pulmonary disease	DISQCIRF	Strong	Altered Expression	[5]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[6]
Hepatitis	DISXXX35	Strong	Altered Expression	[2]
Hepatitis A virus infection	DISUMFQV	Strong	Altered Expression	[2]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Altered Expression	[5]
Obesity	DIS47Y1K	Strong	Biomarker	[7]
Pneumonia	DIS8EF3M	Strong	Biomarker	[4]
Pneumonitis	DIS88E0K	Strong	Biomarker	[4]
Pulmonary fibrosis	DISQKVLA	Strong	Biomarker	[8]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[9]
Autoimmune disease	DISORMTM	Limited	Biomarker	[10]
Hepatocellular carcinoma	DIS0J828	Limited	Biomarker	[11]
Nervous system inflammation	DISB3X5A	Limited	Altered Expression	[10]

11 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 Serine/threonine-protein phosphatase PGAM5, mitochondrial (PGAM5).	[12]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Serine/threonine-protein phosphatase PGAM5, mitochondrial (PGAM5).	[13]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Serine/threonine-protein phosphatase PGAM5, mitochondrial (PGAM5).	[14]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Serine/threonine-protein phosphatase PGAM5, mitochondrial (PGAM5).	[15]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Serine/threonine-protein phosphatase PGAM5, mitochondrial (PGAM5).	[16]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Serine/threonine-protein phosphatase PGAM5, mitochondrial (PGAM5).	[17]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Serine/threonine-protein phosphatase PGAM5, mitochondrial (PGAM5).	[18]
Cannabidiol	DM0659E	Approved	Cannabidiol decreases the expression of Serine/threonine-protein phosphatase PGAM5, mitochondrial (PGAM5).	[19]
Clozapine	DMFC71L	Approved	Clozapine decreases the expression of Serine/threonine-protein phosphatase PGAM5, mitochondrial (PGAM5).	[19]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Serine/threonine-protein phosphatase PGAM5, mitochondrial (PGAM5).	[16]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Serine/threonine-protein phosphatase PGAM5, mitochondrial (PGAM5).	[21]

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 increases the methylation of Serine/threonine-protein phosphatase PGAM5, mitochondrial (PGAM5).	[20]

References

• [1] RIPK1-mediated induction of mitophagy compromises the viability of extracellular-matrix-detached cells.Nat Cell Biol. 2018 Mar;20(3):272-284. doi: 10.1038/s41556-018-0034-2. Epub 2018 Feb 19.
• [2] PGAM5-mediated programmed necrosis of hepatocytes drives acute liver injury.Gut. 2017 Apr;66(4):716-723. doi: 10.1136/gutjnl-2015-311247. Epub 2016 Aug 26.
• [3] PGAM5 regulates PINK1/Parkin-mediated mitophagy via DRP1 in CCCP-induced mitochondrial dysfunction.Toxicol Lett. 2018 Mar 1;284:120-128. doi: 10.1016/j.toxlet.2017.12.004. Epub 2017 Dec 11.
• [4] Oxeiptosis, a ROS-induced caspase-independent apoptosis-like cell-death pathway.Nat Immunol. 2018 Feb;19(2):130-140. doi: 10.1038/s41590-017-0013-y. Epub 2017 Dec 18.
• [5] PGAM5 expression and macrophage signatures in non-small cell lung cancer associated with chronic obstructive pulmonary disease (COPD).BMC Cancer. 2018 Dec 10;18(1):1238. doi: 10.1186/s12885-018-5140-9.
• [6] The ratio of thioredoxin/Keap1 protein level is a predictor of distant metastasis in colorectal cancer.Biomark Med. 2017 Dec;11(12):1103-1111. doi: 10.2217/bmm-2017-0107. Epub 2017 Oct 20.
• [7] The Ablation of Mitochondrial Protein Phosphatase Pgam5 Confers Resistance Against Metabolic Stress.EBioMedicine. 2016 Jan 29;5:82-92. doi: 10.1016/j.ebiom.2016.01.031. eCollection 2016 Mar.
• [8] PGAM5 is a key driver of mitochondrial dysfunction in experimental lung fibrosis.Cell Mol Life Sci. 2019 Dec;76(23):4783-4794. doi: 10.1007/s00018-019-03133-1. Epub 2019 Jun 5.
• [9] PHB2 (prohibitin 2) promotes PINK1-PRKN/Parkin-dependent mitophagy by the PARL-PGAM5-PINK1 axis.Autophagy. 2020 Mar;16(3):419-434. doi: 10.1080/15548627.2019.1628520. Epub 2019 Jun 16.
• [10] Butylphthalide ameliorates experimental autoimmune encephalomyelitis by suppressing PGAM5-induced necroptosis and inflammation in microglia.Biochem Biophys Res Commun. 2018 Feb 26;497(1):80-86. doi: 10.1016/j.bbrc.2018.02.024. Epub 2018 Feb 3.
• [11] High PGAM5 expression induces chemoresistance by enhancing Bcl-xL-mediated anti-apoptotic signaling and predicts poor prognosis in hepatocellular carcinoma patients.Cell Death Dis. 2018 Sep 24;9(10):991. doi: 10.1038/s41419-018-1017-8.
• [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] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [15] 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.
• [16] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
• [17] 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.
• [18] Proteomics-based identification of differentially abundant proteins from human keratinocytes exposed to arsenic trioxide. J Proteomics Bioinform. 2014 Jul;7(7):166-178.
• [19] Cannabidiol Displays Proteomic Similarities to Antipsychotics in Cuprizone-Exposed Human Oligodendrocytic Cell Line MO3.13. Front Mol Neurosci. 2021 May 28;14:673144. doi: 10.3389/fnmol.2021.673144. eCollection 2021.
• [20] 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.
• [21] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.