Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTPZKWN7)

• DOT Name: ATPase family gene 2 protein homolog A (AFG2A)
• Synonyms: EC 3.6.4.10; AFG2 AAA ATPase homolog A; Ribosome biogenesis protein SPATA5; Spermatogenesis-associated factor protein; Spermatogenesis-associated protein 5
• Gene Name: AFG2A
• Related Disease: Microcephaly-intellectual disability-sensorineural hearing loss-epilepsy-abnormal muscle tone syndrome
• UniProt ID: AFG2A_HUMAN
• EC Number: 3.6.4.10
• Pfam ID: PF00004 ; PF17862
• Sequence:
  MSSKKNRKRLNQSAENGSSLPSAASSCAEARAPSAGSDFAATSGTLTVTNLLEKVDDKIP
  KTFQNSLIHLGLNTMKSANICIGRPVLLTSLNGKQEVYTAWPMAGFPGGKVGLSEMAQKN
  VGVRPGDAIQVQPLVGAVLQAEEMDVALSDKDMEINEEELTGCILRKLDGKIVLPGNFLY
  CTFYGRPYKLQVLRVKGADGMILGGPQSDSDTDAQRMAFEQSSMETSSLELSLQLSQLDL
  EDTQIPTSRSTPYKPIDDRITNKASDVLLDVTQSPGDGSGLMLEEVTGLKCNFESAREGN
  EQLTEEERLLKFSIGAKCNTDTFYFISSTTRVNFTEIDKNSKEQDNQFKVTYDMIGGLSS
  QLKAIREIIELPLKQPELFKSYGIPAPRGVLLYGPPGTGKTMIARAVANEVGAYVSVING
  PEIISKFYGETEAKLRQIFAEATLRHPSIIFIDELDALCPKREGAQNEVEKRVVASLLTL
  MDGIGSEVSEGQVLVLGATNRPHALDAALRRPGRFDKEIEIGVPNAQDRLDILQKLLRRV
  PHLLTEAELLQLANSAHGYVGADLKVLCNEAGLCALRRILKKQPNLPDVKVAGLVKITLK
  DFLQAMNDIRPSAMREIAIDVPNVSWSDIGGLESIKLKLEQAVEWPLKHPESFIRMGIQP
  PKGVLLYGPPGCSKTMIAKALANESGLNFLAIKGPELMNKYVGESERAVRETFRKARAVA
  PSIIFFDELDALAVERGSSLGAGNVADRVLAQLLTEMDGIEQLKDVTILAATNRPDRIDK
  ALMRPGRIDRIIYVPLPDAATRREIFKLQFHSMPVSNEVDLDELILQTDAYSGAEIVAVC
  REAALLALEEDIQANLIMKRHFTQALSTVTPRIPESLRRFYEDYQEKSGLHTL
• Function: ATP-dependent chaperone, which plays an essential role in the cytoplasmic maturation steps of pre-60S ribosomal particles by promoting the release of shuttling protein RSL24D1/RLP24 from the pre-ribosomal particles. Acts together with AFG2B, AIRIM and CINP. May be involved in morphological and functional mitochondrial transformations during spermatogenesis.
• KEGG Pathway: Ribosome biogenesis in eukaryotes (hsa03008)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Microcephaly-intellectual disability-sensorineural hearing loss-epilepsy-abnormal muscle tone syndrome	DISDRNZ2	Definitive	Autosomal recessive	[1]

10 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 ATPase family gene 2 protein homolog A (AFG2A).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of ATPase family gene 2 protein homolog A (AFG2A).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of ATPase family gene 2 protein homolog A (AFG2A).	[4]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of ATPase family gene 2 protein homolog A (AFG2A).	[5]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of ATPase family gene 2 protein homolog A (AFG2A).	[6]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of ATPase family gene 2 protein homolog A (AFG2A).	[6]
Bortezomib	DMNO38U	Approved	Bortezomib increases the expression of ATPase family gene 2 protein homolog A (AFG2A).	[7]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of ATPase family gene 2 protein homolog A (AFG2A).	[8]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of ATPase family gene 2 protein homolog A (AFG2A).	[9]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of ATPase family gene 2 protein homolog A (AFG2A).	[10]

References

• [1] Mutations in SPATA5 Are Associated with Microcephaly, Intellectual Disability, Seizures, and Hearing Loss. Am J Hum Genet. 2015 Sep 3;97(3):457-64. doi: 10.1016/j.ajhg.2015.07.014. Epub 2015 Aug 20.
• [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] 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.
• [4] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [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] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [7] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [8] 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.
• [9] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [10] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.