Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT4RULP5)

• DOT Name: Thioredoxin domain-containing protein 3 (NME8)
• Synonyms: 3'-5' exonuclease NME8; EC 3.1.-.-; NM23-H8; NME/NM23 family member 8; Spermatid-specific thioredoxin-2; Sptrx-2
• Gene Name: NME8
• Related Disease:
  Alzheimer disease
  Knee osteoarthritis
  Male infertility
  Osteoarthritis
  Primary ciliary dyskinesia
  Periodontitis
  Primary ciliary dyskinesia 6
• UniProt ID: TXND3_HUMAN
• EC Number: 3.1.-.-
• Pfam ID: PF00334 ; PF00085
• Sequence:
  MASKKREVQLQTVINNQSLWDEMLQNKGLTVIDVYQAWCGPCRAMQPLFRKLKNELNEDE
  ILHFAVAEADNIVTLQPFRDKCEPVFLFSVNGKIIEKIQGANAPLVNKKVINLIDEERKI
  AAGEMARPQYPEIPLVDSDSEVSEESPCESVQELYSIAIIKPDAVISKKVLEIKRKITKA
  GFIIEAEHKTVLTEEQVVNFYSRIADQCDFEEFVSFMTSGLSYILVVSQGSKHNPPSEET
  EPQTDTEPNERSEDQPEVEAQVTPGMMKNKQDSLQEYLERQHLAQLCDIEEDAANVAKFM
  DAFFPDFKKMKSMKLEKTLALLRPNLFHERKDDVLRIIKDEDFKILEQRQVVLSEKEAQA
  LCKEYENEDYFNKLIENMTSGPSLALVLLRDNGLQYWKQLLGPRTVEEAIEYFPESLCAQ
  FAMDSLPVNQLYGSDSLETAEREIQHFFPLQSTLGLIKPHATSEQREQILKIVKEAGFDL
  TQVKKMFLTPEQIEKIYPKVTGKDFYKDLLEMLSVGPSMVMILTKWNAVAEWRRLMGPTD
  PEEAKLLSPDSIRAQFGISKLKNIVHGASNAYEAKEVVNRLFEDPEEN
• Function: Probably required during the final stages of sperm tail maturation in the testis and/or epididymis, where extensive disulfide bonding of fibrous sheath (FS) proteins occurs. In vitro, it has neither nucleoside diphosphate kinase (NDPK) activity nor reducing activity on disulfide bonds. Exhibits a 3'-5' exonuclease activity with a preference for single-stranded DNA, suggesting roles in DNA proofreading and repair.
• Tissue Specificity: Testis-specific. Expressed only in primary spermatocytes and round spermatids.

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]
Knee osteoarthritis	DISLSNBJ	Strong	Genetic Variation	[2]
Male infertility	DISY3YZZ	Strong	Biomarker	[3]
Osteoarthritis	DIS05URM	Strong	Biomarker	[4]
Primary ciliary dyskinesia	DISOBC7V	Supportive	Autosomal dominant	[5]
Periodontitis	DISI9JOI	Limited	Genetic Variation	[6]
Primary ciliary dyskinesia 6	DISZ7307	Limited	Autosomal recessive	[7]

9 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 Thioredoxin domain-containing protein 3 (NME8).	[8]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Thioredoxin domain-containing protein 3 (NME8).	[9]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Thioredoxin domain-containing protein 3 (NME8).	[10]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Thioredoxin domain-containing protein 3 (NME8).	[10]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Thioredoxin domain-containing protein 3 (NME8).	[11]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of Thioredoxin domain-containing protein 3 (NME8).	[12]
Belinostat	DM6OC53	Phase 2	Belinostat increases the expression of Thioredoxin domain-containing protein 3 (NME8).	[10]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Thioredoxin domain-containing protein 3 (NME8).	[14]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Thioredoxin domain-containing protein 3 (NME8).	[15]

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 Thioredoxin domain-containing protein 3 (NME8).	[13]

References

• [1] Association and interaction effects of Alzheimer's disease-associated genes and lifestyle on cognitive aging in older adults in a Taiwanese population.Oncotarget. 2017 Apr 11;8(15):24077-24087. doi: 10.18632/oncotarget.15269.
• [2] Association of single-nucleotide polymorphisms in RHOB and TXNDC3 with knee osteoarthritis susceptibility: two case-control studies in East Asian populations and a meta-analysis.Arthritis Res Ther. 2008;10(3):R54. doi: 10.1186/ar2423. Epub 2008 May 10.
• [3] A common variant in combination with a nonsense mutation in a member of the thioredoxin family causes primary ciliary dyskinesia. Proc Natl Acad Sci U S A. 2007 Feb 27;104(9):3336-41. doi: 10.1073/pnas.0611405104. Epub 2007 Feb 20.
• [4] Genetic association analysis of RHOB and TXNDC3 in osteoarthritis.Am J Hum Genet. 2007 Feb;80(2):383-6; author reply 386-7. doi: 10.1086/511443.
• [5] Primary Ciliary Dyskinesia. 2007 Jan 24 [updated 2019 Dec 5]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews(?) [Internet]. Seattle (WA): University of Washington, Seattle; 1993C2024.
• [6] A genome-wide association study of periodontitis in a Japanese population.J Dent Res. 2015 Apr;94(4):555-61. doi: 10.1177/0022034515570315. Epub 2015 Feb 11.
• [7] 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.
• [8] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [9] 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.
• [10] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [11] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [12] Identification by automated screening of a small molecule that selectively eliminates neural stem cells derived from hESCs but not dopamine neurons. PLoS One. 2009 Sep 23;4(9):e7155.
• [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] BET bromodomain inhibition targets both c-Myc and IL7R in high-risk acute lymphoblastic leukemia. Blood. 2012 Oct 4;120(14):2843-52.
• [15] 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.