Details of Drug Off-Target (DOT)

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

• DOT Name: Propionyl-CoA carboxylase alpha chain, mitochondrial (PCCA)
• Synonyms: PCCase subunit alpha; EC 6.4.1.3; Propanoyl-CoA:carbon dioxide ligase subunit alpha
• Gene Name: PCCA
• Related Disease: Propionic acidemia
• UniProt ID: PCCA_HUMAN
• PDB ID: 2CQY; 2JKU; 7YBU
• EC Number: 6.4.1.3
• Pfam ID: PF02785 ; PF00289 ; PF00364 ; PF02786 ; PF18140
• Sequence:
  MAGFWVGTAPLVAAGRRGRWPPQQLMLSAALRTLKHVLYYSRQCLMVSRNLGSVGYDPNE
  KTFDKILVANRGEIACRVIRTCKKMGIKTVAIHSDVDASSVHVKMADEAVCVGPAPTSKS
  YLNMDAIMEAIKKTRAQAVHPGYGFLSENKEFARCLAAEDVVFIGPDTHAIQAMGDKIES
  KLLAKKAEVNTIPGFDGVVKDAEEAVRIAREIGYPVMIKASAGGGGKGMRIAWDDEETRD
  GFRLSSQEAASSFGDDRLLIEKFIDNPRHIEIQVLGDKHGNALWLNERECSIQRRNQKVV
  EEAPSIFLDAETRRAMGEQAVALARAVKYSSAGTVEFLVDSKKNFYFLEMNTRLQVEHPV
  TECITGLDLVQEMIRVAKGYPLRHKQADIRINGWAVECRVYAEDPYKSFGLPSIGRLSQY
  QEPLHLPGVRVDSGIQPGSDISIYYDPMISKLITYGSDRTEALKRMADALDNYVIRGVTH
  NIALLREVIINSRFVKGDISTKFLSDVYPDGFKGHMLTKSEKNQLLAIASSLFVAFQLRA
  QHFQENSRMPVIKPDIANWELSVKLHDKVHTVVASNNGSVFSVEVDGSKLNVTSTWNLAS
  PLLSVSVDGTQRTVQCLSREAGGNMSIQFLGTVYKVNILTRLAAELNKFMLEKVTEDTSS
  VLRSPMPGVVVAVSVKPGDAVAEGQEICVIEAMKMQNSMTAGKTGTVKSVHCQAGDTVGE
  GDLLVELE
• Function: This is one of the 2 subunits of the biotin-dependent propionyl-CoA carboxylase (PCC), a mitochondrial enzyme involved in the catabolism of odd chain fatty acids, branched-chain amino acids isoleucine, threonine, methionine, and valine and other metabolites. Propionyl-CoA carboxylase catalyzes the carboxylation of propionyl-CoA/propanoyl-CoA to D-methylmalonyl-CoA/(S)-methylmalonyl-CoA. Within the holoenzyme, the alpha subunit catalyzes the ATP-dependent carboxylation of the biotin carried by the biotin carboxyl carrier (BCC) domain, while the beta subunit then transfers the carboxyl group from carboxylated biotin to propionyl-CoA. Propionyl-CoA carboxylase also significantly acts on butyryl-CoA/butanoyl-CoA, which is converted to ethylmalonyl-CoA/(2S)-ethylmalonyl-CoA at a much lower rate. Other alternative minor substrates include (2E)-butenoyl-CoA/crotonoyl-CoA.
• KEGG Pathway:
  Valine, leucine and isoleucine degradation (hsa00280)
  Glyoxylate and dicarboxylate metabolism (hsa00630)
  Propanoate metabolism (hsa00640)
  Metabolic pathways (hsa01100)
  Carbon metabolism (hsa01200)
• Reactome Pathway:
  Defective HLCS causes multiple carboxylase deficiency (R-HSA-3371599)
  Propionyl-CoA catabolism (R-HSA-71032)
  Biotin transport and metabolism (R-HSA-196780)
• BioCyc Pathway: MetaCyc:ENSG00000175198-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Propionic acidemia	DIS56N48	Definitive	Autosomal recessive	[1]

1 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 Propionyl-CoA carboxylase alpha chain, mitochondrial (PCCA).	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Propionyl-CoA carboxylase alpha chain, mitochondrial (PCCA).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Propionyl-CoA carboxylase alpha chain, mitochondrial (PCCA).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Propionyl-CoA carboxylase alpha chain, mitochondrial (PCCA).	[5]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Propionyl-CoA carboxylase alpha chain, mitochondrial (PCCA).	[6]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Propionyl-CoA carboxylase alpha chain, mitochondrial (PCCA).	[7]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Propionyl-CoA carboxylase alpha chain, mitochondrial (PCCA).	[8]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Propionyl-CoA carboxylase alpha chain, mitochondrial (PCCA).	[9]
Progesterone	DMUY35B	Approved	Progesterone decreases the expression of Propionyl-CoA carboxylase alpha chain, mitochondrial (PCCA).	[10]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Propionyl-CoA carboxylase alpha chain, mitochondrial (PCCA).	[11]
Paclitaxel	DMLB81S	Approved	Paclitaxel decreases the expression of Propionyl-CoA carboxylase alpha chain, mitochondrial (PCCA).	[12]
Ethinyl estradiol	DMODJ40	Approved	Ethinyl estradiol increases the expression of Propionyl-CoA carboxylase alpha chain, mitochondrial (PCCA).	[13]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Propionyl-CoA carboxylase alpha chain, mitochondrial (PCCA).	[14]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Propionyl-CoA carboxylase alpha chain, mitochondrial (PCCA).	[15]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Propionyl-CoA carboxylase alpha chain, mitochondrial (PCCA).	[16]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Propionyl-CoA carboxylase alpha chain, mitochondrial (PCCA).	[17]
GALLICACID	DM6Y3A0	Investigative	GALLICACID decreases the expression of Propionyl-CoA carboxylase alpha chain, mitochondrial (PCCA).	[18]

References

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• [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] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [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] Increased mitochondrial ROS formation by acetaminophen in human hepatic cells is associated with gene expression changes suggesting disruption of the mitochondrial electron transport chain. Toxicol Lett. 2015 Apr 16;234(2):139-50.
• [6] 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.
• [7] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [8] 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.
• [9] Chronic occupational exposure to arsenic induces carcinogenic gene signaling networks and neoplastic transformation in human lung epithelial cells. Toxicol Appl Pharmacol. 2012 Jun 1;261(2):204-16.
• [10] Endometrial receptivity is affected in women with high circulating progesterone levels at the end of the follicular phase: a functional genomics analysis. Hum Reprod. 2011 Jul;26(7):1813-25.
• [11] 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.
• [12] Proteomic analysis of anti-cancer effects by paclitaxel treatment in cervical cancer cells. Gynecol Oncol. 2005 Jul;98(1):45-53. doi: 10.1016/j.ygyno.2005.04.010.
• [13] The genomic response of a human uterine endometrial adenocarcinoma cell line to 17alpha-ethynyl estradiol. Toxicol Sci. 2009 Jan;107(1):40-55.
• [14] Dose- and time-dependent transcriptional response of Ishikawa cells exposed to genistein. Toxicol Sci. 2016 May;151(1):71-87.
• [15] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [16] Low-dose Bisphenol A exposure alters the functionality and cellular environment in a human cardiomyocyte model. Environ Pollut. 2023 Oct 15;335:122359. doi: 10.1016/j.envpol.2023.122359. Epub 2023 Aug 9.
• [17] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [18] Gene expression profile analysis of gallic acid-induced cell death process. Sci Rep. 2021 Aug 18;11(1):16743. doi: 10.1038/s41598-021-96174-1.