Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTF36NBP)

• DOT Name: ATP-dependent RNA helicase DDX25 (DDX25)
• Synonyms: EC 3.6.4.13; DEAD box protein 25; Gonadotropin-regulated testicular RNA helicase
• Gene Name: DDX25
• Related Disease:
  Alzheimer disease
  Azoospermia
  Hydrolethalus syndrome
  Male infertility
  Oligospermia
  Obsolete male infertility with azoospermia or oligozoospermia due to single gene mutation
  Generalized resistance to thyroid hormone
• UniProt ID: DDX25_HUMAN
• PDB ID: 2RB4
• EC Number: 3.6.4.13
• Pfam ID: PF00270 ; PF00271
• Sequence:
  MASLLWGGDAGAAESERLNSHFSNLSQPRKNLWGIKSTAVRNIDGSINNINEDDEEDVVD
  LAANSLLNKLIHQSLVESSHRVEVLQKDPSSPLYSVKTFEELRLKEELLKGIYAMGFNRP
  SKIQEMALPMMLAHPPQNLIAQSQSGTGKTAAFVLAMLSRVNALELFPQCLCLAPTYELA
  LQTGRVVEQMGKFCVDVQVMYAIRGNRIPRGTDITKQIIIGTPGTVLDWCFKLKLIDLTK
  IRVFVLDEADVMIDTQGFSDHSIRIQRALPSECQMLLFSATFEDSVWHFAERIIPDPNVI
  KLRKEELTLNNIRQYYVLCEHRKDKYQALCNIYGSITIGQAIIFCQTRRNAKWLTVEMIQ
  DGHQVSLLSGELTVEQRASIIQRFRDGKEKVLITTNVCARGIDVKQVTIVVNFDLPVKQG
  EEPDYETYLHRIGRTGRFGKKGLAFNMIEVDELPSLMKIQDHFNSSIKQLNAEDMDEIEK
  IDY
• Function: ATP-dependent RNA helicase. Required for mRNA export and translation regulation during spermatid development.
• Tissue Specificity: Highly expressed in the Leydig and germ cells of the testis and weakly expressed in the pituitary and hypothalamus.

Molecular Interaction Atlas (MIA) of This DOT

7 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Alzheimer disease	DISF8S70	Strong	Genetic Variation	[1]
Azoospermia	DIS94181	Strong	Biomarker	[2]
Hydrolethalus syndrome	DISX56R3	Strong	Genetic Variation	[3]
Male infertility	DISY3YZZ	Strong	Genetic Variation	[4]
Oligospermia	DIS6YJF3	Strong	Genetic Variation	[5]
Obsolete male infertility with azoospermia or oligozoospermia due to single gene mutation	DIS56JR8	Moderate	Autosomal recessive	[6]
Generalized resistance to thyroid hormone	DIS4TOK0	Disputed	Biomarker	[7]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of ATP-dependent RNA helicase DDX25 (DDX25).	[8]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of ATP-dependent RNA helicase DDX25 (DDX25).	[9]
Cisplatin	DMRHGI9	Approved	Cisplatin affects the expression of ATP-dependent RNA helicase DDX25 (DDX25).	[10]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of ATP-dependent RNA helicase DDX25 (DDX25).	[11]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of ATP-dependent RNA helicase DDX25 (DDX25).	[12]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of ATP-dependent RNA helicase DDX25 (DDX25).	[10]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of ATP-dependent RNA helicase DDX25 (DDX25).	[14]

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 increases the methylation of ATP-dependent RNA helicase DDX25 (DDX25).	[13]

References

• [1] Family-based association analyses of imputed genotypes reveal genome-wide significant association of Alzheimer's disease with OSBPL6, PTPRG, and PDCL3.Mol Psychiatry. 2016 Nov;21(11):1608-1612. doi: 10.1038/mp.2015.218. Epub 2016 Feb 2.
• [2] Gonadotropin Regulation Testicular RNA Helicase, Two Decades of Studies on Its Structure Function and Regulation From Its Discovery Opens a Window for Development of a Non-hormonal Oral Male Contraceptive.Front Endocrinol (Lausanne). 2019 Aug 29;10:576. doi: 10.3389/fendo.2019.00576. eCollection 2019.
• [3] Hydrolethalus syndrome is caused by a missense mutation in a novel gene HYLS1. Hum Mol Genet. 2005 Jun 1;14(11):1475-88. doi: 10.1093/hmg/ddi157. Epub 2005 Apr 20.
• [4] Association of the gonadotrophin-regulated testicular RNA helicase gene polymorphism with human male infertility.Andrologia. 2014;46(9):1063-6. doi: 10.1111/and.12185. Epub 2013 Oct 29.
• [5] Single nucleotide polymorphisms of the gonadotrophin-regulated testicular helicase (GRTH) gene may be associated with the human spermatogenesis impairment.Hum Reprod. 2006 Mar;21(3):755-9. doi: 10.1093/humrep/dei388. Epub 2005 Nov 17.
• [6] A genomics approach to male infertility. Genet Med. 2020 Dec;22(12):1967-1975. doi: 10.1038/s41436-020-0916-0. Epub 2020 Jul 28.
• [7] Differential expression of mutant and normal beta T3 receptor alleles in kindreds with generalized resistance to thyroid hormone.J Clin Invest. 1993 May;91(5):2296-300. doi: 10.1172/JCI116458.
• [8] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [9] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [10] Acute hypersensitivity of pluripotent testicular cancer-derived embryonal carcinoma to low-dose 5-aza deoxycytidine is associated with global DNA Damage-associated p53 activation, anti-pluripotency and DNA demethylation. PLoS One. 2012;7(12):e53003. doi: 10.1371/journal.pone.0053003. Epub 2012 Dec 27.
• [11] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [12] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [13] 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.
• [14] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.