Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTOMEQX6)

• DOT Name: ATP synthase mitochondrial F1 complex assembly factor 2 (ATPAF2)
• Synonyms: ATP12 homolog
• Gene Name: ATPAF2
• Related Disease:
  Dementia
  Coronary heart disease
  Mitochondrial proton-transporting ATP synthase complex deficiency
  Mitochondrial complex V (ATP synthase) deficiency, nuclear type 1
  Mitochondrial disease
• UniProt ID: ATPF2_HUMAN
• Pfam ID: PF07542
• Sequence:
  MWRSCLRLRDGGRRLLNRPAGGPSASMSPGPTIPSPARAYAPPTERKRFYQNVSITQGEG
  GFEINLDHRKLKTPQAKLFTVPSEALAIAVATEWDSQQDTIKYYTMHLTTLCNTSLDNPT
  QRNKDQLIRAAVKFLDTDTICYRVEEPETLVELQRNEWDPIIEWAEKRYGVEISSSTSIM
  GPSIPAKTREVLVSHLASYNTWALQGIEFVAAQLKSMVLTLGLIDLRLTVEQAVLLSRLE
  EEYQIQKWGNIEWAHDYELQELRARTAAGTLFIHLCSESTTVKHKLLKE
• Function: May play a role in the assembly of the F1 component of the mitochondrial ATP synthase (ATPase).
• Tissue Specificity: Widely expressed.
• BioCyc Pathway: MetaCyc:ENSG00000171953-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Dementia	DISXL1WY	Strong	Biomarker	[1]
Coronary heart disease	DIS5OIP1	moderate	Genetic Variation	[2]
Mitochondrial proton-transporting ATP synthase complex deficiency	DISX6N3H	Supportive	Autosomal recessive	[3]
Mitochondrial complex V (ATP synthase) deficiency, nuclear type 1	DIS5R3EL	Limited	Autosomal recessive	[3]
Mitochondrial disease	DISKAHA3	Limited	Autosomal recessive	[4]

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 ATP synthase mitochondrial F1 complex assembly factor 2 (ATPAF2).	[5]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of ATP synthase mitochondrial F1 complex assembly factor 2 (ATPAF2).	[9]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin affects the expression of ATP synthase mitochondrial F1 complex assembly factor 2 (ATPAF2).	[6]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of ATP synthase mitochondrial F1 complex assembly factor 2 (ATPAF2).	[7]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of ATP synthase mitochondrial F1 complex assembly factor 2 (ATPAF2).	[8]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene affects the expression of ATP synthase mitochondrial F1 complex assembly factor 2 (ATPAF2).	[6]

References

• [1] Analysis of lipid pathway genes indicates association of sequence variation near SREBF1/TOM1L2/ATPAF2 with dementia risk.Hum Mol Genet. 2010 May 15;19(10):2068-78. doi: 10.1093/hmg/ddq079. Epub 2010 Feb 18.
• [2] Large-scale association analysis identifies new risk loci for coronary artery disease.Nat Genet. 2013 Jan;45(1):25-33. doi: 10.1038/ng.2480. Epub 2012 Dec 2.
• [3] Respiratory chain complex V deficiency due to a mutation in the assembly gene ATP12. J Med Genet. 2004 Feb;41(2):120-4. doi: 10.1136/jmg.2003.012047.
• [4] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [5] 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.
• [6] Differential modulation of PI3-kinase/Akt pathway during all-trans retinoic acid- and Am80-induced HL-60 cell differentiation revealed by DNA microarray analysis. Biochem Pharmacol. 2004 Dec 1;68(11):2177-86.
• [7] 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.
• [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] 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.