Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTAJDLE2)

• DOT Name: ATP synthase subunit d, mitochondrial (ATP5PD)
• Synonyms: ATPase subunit d; ATP synthase peripheral stalk subunit d
• Gene Name: ATP5PD
• Related Disease:
  Advanced cancer
  Alzheimer disease
  Congenital hypothyroidism
  Lung adenocarcinoma
  Neoplasm
  Schizophrenia
  Hepatocellular carcinoma
• UniProt ID: ATP5H_HUMAN
• PDB ID: 8H9F; 8H9G; 8H9J; 8H9K; 8H9M; 8H9N; 8H9Q; 8H9R; 8H9S; 8H9T; 8H9U; 8H9V
• Pfam ID: PF05873
• Sequence:
  MAGRKLALKTIDWVAFAEIIPQNQKAIASSLKSWNETLTSRLAALPENPPAIDWAYYKAN
  VAKAGLVDDFEKKFNALKVPVPEDKYTAQVDAEEKEDVKSCAEWVSLSKARIVEYEKEME
  KMKNLIPFDQMTIEDLNEAFPETKLDKKKYPYWPHQPIENL
• 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(0) domain and the peripheric stalk, which acts as a stator to hold the catalytic alpha(3)beta(3) subcomplex and subunit a/ATP6 static relative to the rotary elements.
• 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:HS09654-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

7 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Alzheimer disease	DISF8S70	Strong	Genetic Variation	[2]
Congenital hypothyroidism	DISL5XVU	Strong	Biomarker	[3]
Lung adenocarcinoma	DISD51WR	Strong	Biomarker	[4]
Neoplasm	DISZKGEW	Strong	Biomarker	[1]
Schizophrenia	DISSRV2N	Strong	Altered Expression	[5]
Hepatocellular carcinoma	DIS0J828	Limited	Biomarker	[6]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Josamycin	DMKJ8LB	Approved	ATP synthase subunit d, mitochondrial (ATP5PD) affects the response to substance of Josamycin.	[19]

11 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 ATP synthase subunit d, mitochondrial (ATP5PD).	[7]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of ATP synthase subunit d, mitochondrial (ATP5PD).	[8]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of ATP synthase subunit d, mitochondrial (ATP5PD).	[9]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of ATP synthase subunit d, mitochondrial (ATP5PD).	[10]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide decreases the expression of ATP synthase subunit d, mitochondrial (ATP5PD).	[11]
Selenium	DM25CGV	Approved	Selenium decreases the expression of ATP synthase subunit d, mitochondrial (ATP5PD).	[12]
Sodium lauryl sulfate	DMLJ634	Approved	Sodium lauryl sulfate increases the expression of ATP synthase subunit d, mitochondrial (ATP5PD).	[13]
Dopamine	DMPGUCF	Approved	Dopamine increases the expression of ATP synthase subunit d, mitochondrial (ATP5PD).	[14]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of ATP synthase subunit d, mitochondrial (ATP5PD).	[16]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of ATP synthase subunit d, mitochondrial (ATP5PD).	[17]
chloropicrin	DMSGBQA	Investigative	chloropicrin increases the expression of ATP synthase subunit d, mitochondrial (ATP5PD).	[18]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of ATP synthase subunit d, mitochondrial (ATP5PD).	[15]

References

• [1] Mitochondrial reprogramming via ATP5H loss promotes multimodal cancer therapy resistance.J Clin Invest. 2018 Aug 31;128(9):4098-4114. doi: 10.1172/JCI96804. Epub 2018 Aug 20.
• [2] ATP5H/KCTD2 locus is associated with Alzheimer's disease risk.Mol Psychiatry. 2014 Jun;19(6):682-7. doi: 10.1038/mp.2013.86. Epub 2013 Jul 16.
• [3] [Proteomic changes in cerebral cortex of neonatal rats with experimental congenital hypothyroidism].Zhonghua Er Ke Za Zhi. 2011 Mar;49(3):209-13.
• [4] Comparative proteome analysis of human adenocarcinoma.Med Oncol. 2010 Jun;27(2):346-56. doi: 10.1007/s12032-009-9216-x. Epub 2009 Apr 21.
• [5] Proteomic analysis of dorsolateral prefrontal cortex indicates the involvement of cytoskeleton, oligodendrocyte, energy metabolism and new potential markers in schizophrenia.J Psychiatr Res. 2009 Jul;43(11):978-86. doi: 10.1016/j.jpsychires.2008.11.006. Epub 2008 Dec 24.
• [6] Hepatocellular carcinoma-associated protein markers investigated by MALDI-TOF MS.Mol Med Rep. 2010 Jul-Aug;3(4):589-96. doi: 10.3892/mmr_00000302.
• [7] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [8] 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.
• [9] 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.
• [10] 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.
• [11] MS4A3-HSP27 target pathway reveals potential for haematopoietic disorder treatment in alimentary toxic aleukia. Cell Biol Toxicol. 2023 Feb;39(1):201-216. doi: 10.1007/s10565-021-09639-4. Epub 2021 Sep 28.
• [12] 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.
• [13] Identification of potential biomarkers for predicting acute dermal irritation by proteomic analysis. J Appl Toxicol. 2011 Nov;31(8):762-72.
• [14] Mitochondrial proteomics investigation of a cellular model of impaired dopamine homeostasis, an early step in Parkinson's disease pathogenesis. Mol Biosyst. 2014 Jun;10(6):1332-44.
• [15] 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.
• [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] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.
• [19] A genome-wide analysis of targets of macrolide antibiotics in mammalian cells. J Biol Chem. 2020 Feb 14;295(7):2057-2067. doi: 10.1074/jbc.RA119.010770. Epub 2020 Jan 8.