Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTZJW04C)

• DOT Name: PGC-1 and ERR-induced regulator in muscle protein 1 (PERM1)
• Synonyms: PPARGC1 and ESRR-induced regulator in muscle 1; Peroxisome proliferator-activated receptor gamma coactivator 1 and estrogen-related receptor-induced regulator in muscle 1
• Gene Name: PERM1
• Related Disease:
  Myopathy
  Obesity
  Mitochondrial myopathy
• UniProt ID: PERM1_HUMAN
• Sequence:
  MENFQYSVQLSDQDWAEFSATADECGLLQAGLASGDELLSSDIDQGDSSGSSPPRAPPLP
  TGQLAAGGRSRRGCEEEDVATQQPVSRSQGEPVLALGTGQQTPSTSARAEAPPSLGPGAS
  PPSQFSSCPGPASSGDQMQRLLQGPAPRPPGEPPGSPKSPGHSTGSQRPPDSPGAPPRSP
  SRKKRRAVGAKGGGHTGASASAQTGSPLLPAASPETAKLMAKAGQEELGPGPAGAPEPGP
  RSPVQEDRPGPGLGLSTPVPVTEQGTDQIRTPRRAKLHTVSTTVWEALPDVSRAKSDMAV
  STPASEPQPDRDMAVSTPASEPQSDRDMAVSTPASEPQPDTDMAVSTPASEPQPDRDMAV
  SIPASKPQSDTAVSTPASEPQSSVALSTPISKPQLDTDVAVSTPASKHGLDVALPTAGPV
  AKLEVASSPPVSEAVPRMTESSGLVSTPVPRADAAGLAWPPTRRAGPDVVEMEAVVSEPS
  AGAPGCCSGAPALGLTQVPRKKKVRFSVAGPSPNKPGSGQASARPSAPQTATGAHGGPGA
  WEAVAVGPRPHQPRILKHLPRPPPSAVTRVGPGSSFAVTLPEAYEFFFCDTIEENEEAEA
  AAAGQDPAGVQWPDMCEFFFPDVGAQRSRRRGSPEPLPRADPVPAPIPGDPVPISIPEVY
  EHFFFGEDRLEGVLGPAVPLPLQALEPPRSASEGAGPGTPLKPAVVERLHLALRRAGELR
  GPVPSFAFSQNDMCLVFVAFATWAVRTSDPHTPDAWKTALLANVGTISAIRYFRRQVGQG
  RRSHSPSPSS
• Function: Regulates the expression of selective PPARGC1A/B and ESRRA/B/G target genes with roles in glucose and lipid metabolism, energy transfer, contractile function, muscle mitochondrial biogenesis and oxidative capacity. Required for the efficient induction of MT-CO2, MT-CO3, COX4I1, TFB1M, TFB2M, POLRMT and SIRT3 by PPARGC1A. Positively regulates the PPARGC1A/ESRRG-induced expression of CKMT2, TNNI3 and SLC2A4 and negatively regulates the PPARGC1A/ESRRG-induced expression of PDK4.
• Tissue Specificity: Muscle-specific expression is increased by endurance exercise.
• Reactome Pathway: Transcriptional activation of mitochondrial biogenesis (R-HSA-2151201)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Myopathy	DISOWG27	moderate	Biomarker	[1]
Obesity	DIS47Y1K	moderate	Altered Expression	[1]
Mitochondrial myopathy	DIS9SA7V	Limited	Biomarker	[2]

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 PGC-1 and ERR-induced regulator in muscle protein 1 (PERM1).	[3]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of PGC-1 and ERR-induced regulator in muscle protein 1 (PERM1).	[4]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of PGC-1 and ERR-induced regulator in muscle protein 1 (PERM1).	[5]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of PGC-1 and ERR-induced regulator in muscle protein 1 (PERM1).	[6]
KOJIC ACID	DMP84CS	Investigative	KOJIC ACID decreases the expression of PGC-1 and ERR-induced regulator in muscle protein 1 (PERM1).	[7]

References

• [1] Perm1 regulates CaMKII activation and shapes skeletal muscle responses to endurance exercise training.Mol Metab. 2019 May;23:88-97. doi: 10.1016/j.molmet.2019.02.009. Epub 2019 Feb 27.
• [2] Peroxisome proliferator-activated receptor coactivator 1 (PGC-1)- and estrogen-related receptor (ERR)-induced regulator in muscle 1 (Perm1) is a tissue-specific regulator of oxidative capacity in skeletal muscle cells.J Biol Chem. 2013 Aug 30;288(35):25207-25218. doi: 10.1074/jbc.M113.489674. Epub 2013 Jul 8.
• [3] 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.
• [4] 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.
• [5] 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.
• [6] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [7] Toxicogenomics of kojic acid on gene expression profiling of a375 human malignant melanoma cells. Biol Pharm Bull. 2006 Apr;29(4):655-69.