Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTV5GZK5)

• DOT Name: ATP synthase subunit gamma, mitochondrial (ATP5F1C)
• Synonyms: ATP synthase F1 subunit gamma; F-ATPase gamma subunit
• Gene Name: ATP5F1C
• Related Disease:
  Colorectal carcinoma
  Neoplasm
  Schizophrenia
• UniProt ID: ATPG_HUMAN
• PDB ID: 8H9E; 8H9F; 8H9I; 8H9J; 8H9L; 8H9M; 8H9P; 8H9Q; 8H9S; 8H9T; 8H9U; 8H9V
• Pfam ID: PF00231
• Sequence:
  MFSRAGVAGLSAWTLQPQWIQVRNMATLKDITRRLKSIKNIQKITKSMKMVAAAKYARAE
  RELKPARIYGLGSLALYEKADIKGPEDKKKHLLIGVSSDRGLCGAIHSSIAKQMKSEVAT
  LTAAGKEVMLVGIGDKIRGILYRTHSDQFLVAFKEVGRKPPTFGDASVIALELLNSGYEF
  DEGSIIFNKFRSVISYKTEEKPIFSLNTVASADSMSIYDDIDADVLQNYQEYNLANIIYY
  SLKESTTSEQSARMTAMDNASKNASEMIDKLTLTFNRTRQAVITKELIEIISGAAALD
• Function: Mitochondrial membrane ATP synthase (F(1)F(0) ATP synthase or Complex V) produces ATP from ADP in the presence of a proton gradient across the membrane which is generated by electron transport complexes of the respiratory chain. F-type ATPases consist of two structural domains, F(1) - containing the extramembraneous catalytic core, and F(0) - containing the membrane proton channel, linked together by a central stalk and a peripheral stalk. During catalysis, ATP synthesis in the catalytic domain of F(1) is coupled via a rotary mechanism of the central stalk subunits to proton translocation. Part of the complex F(1) domain and the central stalk which is part of the complex rotary element. The gamma subunit protrudes into the catalytic domain formed of alpha(3)beta(3). Rotation of the central stalk against the surrounding alpha(3)beta(3) subunits leads to hydrolysis of ATP in three separate catalytic sites on the beta subunits.
• Tissue Specificity: Isoform Heart is expressed specifically in the heart and skeletal muscle, which require rapid energy supply. Isoform Liver is expressed in the brain, liver and kidney. Isoform Heart and Isoform Liver are expressed in the skin, intestine, stomach and aorta.
• KEGG Pathway:
  Oxidative phosphorylation (hsa00190)
  Metabolic pathways (hsa01100)
  Thermogenesis (hsa04714)
  Alzheimer disease (hsa05010)
  Parkinson disease (hsa05012)
  Amyotrophic lateral sclerosis (hsa05014)
  Huntington disease (hsa05016)
  Prion disease (hsa05020)
  Pathways of neurodegeneration - multiple diseases (hsa05022)
  Chemical carcinogenesis - reactive oxygen species (hsa05208)
  Diabetic cardiomyopathy (hsa05415)
• Reactome Pathway:
  Cristae formation (R-HSA-8949613)
  Formation of ATP by chemiosmotic coupling (R-HSA-163210)
• BioCyc Pathway: MetaCyc:HS09257-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Colorectal carcinoma	DIS5PYL0	Definitive	Genetic Variation	[1]
Neoplasm	DISZKGEW	Definitive	Genetic Variation	[1]
Schizophrenia	DISSRV2N	Strong	Biomarker	[2]

3 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 ATP synthase subunit gamma, mitochondrial (ATP5F1C).	[3]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of ATP synthase subunit gamma, mitochondrial (ATP5F1C).	[12]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of ATP synthase subunit gamma, mitochondrial (ATP5F1C).	[14]

11 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 ATP synthase subunit gamma, mitochondrial (ATP5F1C).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of ATP synthase subunit gamma, mitochondrial (ATP5F1C).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of ATP synthase subunit gamma, mitochondrial (ATP5F1C).	[6]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of ATP synthase subunit gamma, mitochondrial (ATP5F1C).	[7]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of ATP synthase subunit gamma, mitochondrial (ATP5F1C).	[8]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of ATP synthase subunit gamma, mitochondrial (ATP5F1C).	[9]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of ATP synthase subunit gamma, mitochondrial (ATP5F1C).	[10]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of ATP synthase subunit gamma, mitochondrial (ATP5F1C).	[11]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of ATP synthase subunit gamma, mitochondrial (ATP5F1C).	[13]
chloropicrin	DMSGBQA	Investigative	chloropicrin increases the expression of ATP synthase subunit gamma, mitochondrial (ATP5F1C).	[15]
AHPN	DM8G6O4	Investigative	AHPN decreases the expression of ATP synthase subunit gamma, mitochondrial (ATP5F1C).	[16]

References

• [1] cis-Expression QTL analysis of established colorectal cancer risk variants in colon tumors and adjacent normal tissue.PLoS One. 2012;7(2):e30477. doi: 10.1371/journal.pone.0030477. Epub 2012 Feb 17.
• [2] Transcriptomic analysis reveals oxidative phosphorylation activation in an adolescent social isolation rat model.Brain Res Bull. 2018 Sep;142:304-312. doi: 10.1016/j.brainresbull.2018.08.013. Epub 2018 Aug 22.
• [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] 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.
• [5] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [6] 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.
• [7] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [8] 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.
• [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] Temporal changes in gene expression in the skin of patients treated with isotretinoin provide insight into its mechanism of action. Dermatoendocrinol. 2009 May;1(3):177-87.
• [11] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [12] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [13] 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.
• [14] 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.
• [15] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.
• [16] ST1926, a novel and orally active retinoid-related molecule inducing apoptosis in myeloid leukemia cells: modulation of intracellular calcium homeostasis. Blood. 2004 Jan 1;103(1):194-207.