Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT344CQO)

• DOT Name: Phosphopantothenate--cysteine ligase (PPCS)
• Synonyms: EC 6.3.2.51; Phosphopantothenoylcysteine synthetase; PPC synthetase
• Gene Name: PPCS
• Related Disease:
  Familial dilated cardiomyopathy
  Cardiomyopathy, dilated, 2c
  Dilated cardiomyopathy
  Obsolete familial isolated dilated cardiomyopathy
• UniProt ID: PPCS_HUMAN
• PDB ID: 1P9O; 7EDZ
• EC Number: 6.3.2.51
• Pfam ID: PF04127
• Sequence:
  MAEMDPVAEFPQPPGAARWAEVMARFAARLGAQGRRVVLVTSGGTKVPLEARPVRFLDNF
  SSGRRGATSAEAFLAAGYGVLFLYRARSAFPYAHRFPPQTWLSALRPSGPALSGLLSLEA
  EENALPGFAEALRSYQEAAAAGTFLAVEFTTLADYLHLLQAAAQALNPLGPSAMFYLAAA
  VSDFYVPVSEMPEHKIQSSGGPLQITMKMVPKLLSPLVKDWAPKAFIISFKLETDPAIVI
  NRARKALEIYQHQVVVANILESRQSFVFIVTKDSETKLLLSEEEIEKGVEIEEKIVDNLQ
  SRHTAFIGDRN
• Function: Catalyzes the second step in the biosynthesis of coenzyme A from vitamin B5, where cysteine is conjugated to 4'-phosphopantothenate to form 4-phosphopantothenoylcysteine. Has a preference for ATP over CTP as a cosubstrate.
• KEGG Pathway:
  Pantothe.te and CoA biosynthesis (hsa00770)
  Metabolic pathways (hsa01100)
  Biosynthesis of cofactors (hsa01240)
• Reactome Pathway: Coenzyme A biosynthesis (R-HSA-196783)
• BioCyc Pathway: MetaCyc:HS13229-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Familial dilated cardiomyopathy	DISBHDU9	Definitive	GermlineCausalMutation	[1]
Cardiomyopathy, dilated, 2c	DISHQXQL	Strong	Autosomal recessive	[1]
Dilated cardiomyopathy	DISX608J	moderate	Genetic Variation	[1]
Obsolete familial isolated dilated cardiomyopathy	DIS4FXO4	Supportive	Autosomal dominant	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Phosphopantothenate--cysteine ligase (PPCS).	[2]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Phosphopantothenate--cysteine ligase (PPCS).	[9]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Phosphopantothenate--cysteine ligase (PPCS).	[3]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Phosphopantothenate--cysteine ligase (PPCS).	[4]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Phosphopantothenate--cysteine ligase (PPCS).	[5]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Phosphopantothenate--cysteine ligase (PPCS).	[6]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Phosphopantothenate--cysteine ligase (PPCS).	[7]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Phosphopantothenate--cysteine ligase (PPCS).	[8]

References

• [1] Mutations in PPCS, Encoding Phosphopantothenoylcysteine Synthetase, Cause Autosomal-Recessive Dilated Cardiomyopathy. Am J Hum Genet. 2018 Jun 7;102(6):1018-1030. doi: 10.1016/j.ajhg.2018.03.022. Epub 2018 May 10.
• [2] 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.
• [3] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [4] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [5] 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.
• [6] 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.
• [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] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [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.