Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTN6FKCB)

• DOT Name: Peroxisome proliferator-activated receptor gamma coactivator 1-beta (PPARGC1B)
• Synonyms: PGC-1-beta; PPAR-gamma coactivator 1-beta; PPARGC-1-beta; PGC-1-related estrogen receptor alpha coactivator
• Gene Name: PPARGC1B
• UniProt ID: PRGC2_HUMAN
• PDB ID: 3SP6; 6D0Y
• Pfam ID: PF00076
• Sequence:
  MAGNDCGALLDEELSSFFLNYLADTQGGGSGEEQLYADFPELDLSQLDASDFDSATCFGE
  LQWCPENSETEPNQYSPDDSELFQIDSENEALLAELTKTLDDIPEDDVGLAAFPALDGGD
  ALSCTSASPAPSSAPPSPAPEKPSAPAPEVDELSLLQKLLLATSYPTSSSDTQKEGTAWR
  QAGLRSKSQRPCVKADSTQDKKAPMMQSQSRSCTELHKHLTSAQCCLQDRGLQPPCLQSP
  RLPAKEDKEPGEDCPSPQPAPASPRDSLALGRADPGAPVSQEDMQAMVQLIRYMHTYCLP
  QRKLPPQTPEPLPKACSNPSQQVRSRPWSRHHSKASWAEFSILRELLAQDVLCDVSKPYR
  LATPVYASLTPRSRPRPPKDSQASPGRPSSVEEVRIAASPKSTGPRPSLRPLRLEVKREV
  RRPARLQQQEEEDEEEEEEEEEEEKEEEEEWGRKRPGRGLPWTKLGRKLESSVCPVRRSR
  RLNPELGPWLTFADEPLVPSEPQGALPSLCLAPKAYDVERELGSPTDEDSGQDQQLLRGP
  QIPALESPCESGCGDMDEDPSCPQLPPRDSPRCLMLALSQSDPTFGKKSFEQTLTVELCG
  TAGLTPPTTPPYKPTEEDPFKPDIKHSLGKEIALSLPSPEGLSLKATPGAAHKLPKKHPE
  RSELLSHLRHATAQPASQAGQKRPFSCSFGDHDYCQVLRPEGVLQRKVLRSWEPSGVHLE
  DWPQQGAPWAEAQAPGREEDRSCDAGAPPKDSTLLRDHEIRASLTKHFGLLETALEEEDL
  ASCKSPEYDTVFEDSSSSSGESSFLPEEEEEEGEEEEEDDEEEDSGVSPTCSDHCPYQSP
  PSKANRQLCSRSRSSSGSSPCHSWSPATRRNFRCESRGPCSDRTPSIRHARKRREKAIGE
  GRVVYIQNLSSDMSSRELKRRFEVFGEIEECEVLTRNRRGEKYGFITYRCSEHAALSLTK
  GAALRKRNEPSFQLSYGGLRHFCWPRYTDYDSNSEEALPASGKSKYEAMDFDSLLKEAQQ
  SLH
• Function: Plays a role of stimulator of transcription factors and nuclear receptors activities. Activates transcriptional activity of estrogen receptor alpha, nuclear respiratory factor 1 (NRF1) and glucocorticoid receptor in the presence of glucocorticoids. May play a role in constitutive non-adrenergic-mediated mitochondrial biogenesis as suggested by increased basal oxygen consumption and mitochondrial number when overexpressed. May be involved in fat oxidation and non-oxidative glucose metabolism and in the regulation of energy expenditure. Induces the expression of PERM1 in the skeletal muscle in an ESRRA-dependent manner.
• Tissue Specificity: Ubiquitous with higher expression in heart, brain and skeletal muscle.
• KEGG Pathway: Insulin resistance (hsa04931)
• Reactome Pathway:
  Transcriptional activation of mitochondrial biogenesis (R-HSA-2151201)
  Regulation of RUNX2 expression and activity (R-HSA-8939902)
  PPARA activates gene expression (R-HSA-1989781)

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Peroxisome proliferator-activated receptor gamma coactivator 1-beta (PPARGC1B).	[1]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Peroxisome proliferator-activated receptor gamma coactivator 1-beta (PPARGC1B).	[2]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Peroxisome proliferator-activated receptor gamma coactivator 1-beta (PPARGC1B).	[3]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Peroxisome proliferator-activated receptor gamma coactivator 1-beta (PPARGC1B).	[4]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Peroxisome proliferator-activated receptor gamma coactivator 1-beta (PPARGC1B).	[6]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Peroxisome proliferator-activated receptor gamma coactivator 1-beta (PPARGC1B).	[7]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Peroxisome proliferator-activated receptor gamma coactivator 1-beta (PPARGC1B).	[7]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Peroxisome proliferator-activated receptor gamma coactivator 1-beta (PPARGC1B).	[8]
Etoposide	DMNH3PG	Approved	Etoposide increases the expression of Peroxisome proliferator-activated receptor gamma coactivator 1-beta (PPARGC1B).	[9]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Peroxisome proliferator-activated receptor gamma coactivator 1-beta (PPARGC1B).	[8]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Peroxisome proliferator-activated receptor gamma coactivator 1-beta (PPARGC1B).	[4]
Belinostat	DM6OC53	Phase 2	Belinostat increases the expression of Peroxisome proliferator-activated receptor gamma coactivator 1-beta (PPARGC1B).	[8]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Peroxisome proliferator-activated receptor gamma coactivator 1-beta (PPARGC1B).	[11]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Peroxisome proliferator-activated receptor gamma coactivator 1-beta (PPARGC1B).	[12]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Peroxisome proliferator-activated receptor gamma coactivator 1-beta (PPARGC1B).	[8]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Peroxisome proliferator-activated receptor gamma coactivator 1-beta (PPARGC1B).	[14]
Forskolin	DM6ITNG	Investigative	Forskolin increases the expression of Peroxisome proliferator-activated receptor gamma coactivator 1-beta (PPARGC1B).	[15]
Oxalacetic acid	DMPZSV1	Investigative	Oxalacetic acid increases the expression of Peroxisome proliferator-activated receptor gamma coactivator 1-beta (PPARGC1B).	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Peroxisome proliferator-activated receptor gamma coactivator 1-beta (PPARGC1B).	[5]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Peroxisome proliferator-activated receptor gamma coactivator 1-beta (PPARGC1B).	[10]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Peroxisome proliferator-activated receptor gamma coactivator 1-beta (PPARGC1B).	[13]

References

• [1] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [2] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [3] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [4] 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.
• [5] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [6] Quercetin exerts bidirectional regulation effects on the efficacy of tamoxifen in estrogen receptor-positive breast cancer therapy: An in vitro study. Environ Toxicol. 2020 Nov;35(11):1179-1193. doi: 10.1002/tox.22983. Epub 2020 Jun 12.
• [7] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [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] Etoposide induces necrosis through p53-mediated antiapoptosis in human kidney proximal tubule cells. Toxicol Sci. 2015 Nov;148(1):204-19.
• [10] 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.
• [11] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [12] 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.
• [13] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [14] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.
• [15] Coactivation of liver receptor homologue-1 by peroxisome proliferator-activated receptor gamma coactivator-1alpha on aromatase promoter II and its inhibition by activated retinoid X receptor suggest a novel target for breast-specific antiestrogen therapy. Cancer Res. 2005 Dec 15;65(24):11762-70. doi: 10.1158/0008-5472.CAN-05-2792.
• [16] Oxaloacetate enhances neuronal cell bioenergetic fluxes and infrastructure. J Neurochem. 2016 Apr;137(1):76-87. doi: 10.1111/jnc.13545. Epub 2016 Mar 11.