Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTDFQV81)

• DOT Name: Inactive peptidyl-prolyl cis-trans isomerase FKBP6 (FKBP6)
• Synonyms: Inactive PPIase FKBP6; 36 kDa FK506-binding protein; 36 kDa FKBP; FKBP-36; FK506-binding protein 6; FKBP-6; Immunophilin FKBP36
• Gene Name: FKBP6
• Related Disease:
  Amyotrophic lateral sclerosis type 1
  Azoospermia
  Hypercalcaemia
  Male infertility
  Multiple sclerosis
  Spermatogenic failure 77
• UniProt ID: FKBP6_HUMAN
• PDB ID: 3B7X
• Pfam ID: PF00254
• Sequence:
  MGGSALNQGVLEGDDAPGQSLYERLSQRMLDISGDRGVLKDVIREGAGDLVAPDASVLVK
  YSGYLEHMDRPFDSNYFRKTPRLMKLGEDITLWGMELGLLSMRRGELARFLFKPNYAYGT
  LGCPPLIPPNTTVLFEIELLDFLDCAESDKFCALSAEQQDQFPLQKVLKVAATEREFGNY
  LFRQNRFYDAKVRYKRALLLLRRRSAPPEEQHLVEAAKLPVLLNLSFTYLKLDRPTIALC
  YGEQALIIDQKNAKALFRCGQACLLLTEYQKARDFLVRAQKEQPFNHDINNELKKLASCY
  RDYVDKEKEMWHRMFAPCGDGSTAGES
• Function: Has an essential role in spermatogenesis. It is required to repress transposable elements and prevent their mobilization, which is essential for the germline integrity. Acts via the piRNA metabolic process, which mediates the repression of transposable elements during meiosis by forming complexes composed of piRNAs and Piwi proteins and govern the methylation and subsequent repression of transposons. Acts as a co-chaperone via its interaction with HSP90 and is required for the piRNA amplification process, the secondary piRNA biogenesis. May be required together with HSP90 in removal of 16 nucleotide ping-pong by-products from Piwi complexes, possibly facilitating turnover of Piwi complexes.
• Tissue Specificity: Detected in all tissues examined, with higher expression in testis, heart, skeletal muscle, liver, and kidney.
• Reactome Pathway:
  PIWI-interacting RNA (piRNA) biogenesis (R-HSA-5601884)
  Meiotic synapsis (R-HSA-1221632)

Molecular Interaction Atlas (MIA) of This DOT

6 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Amyotrophic lateral sclerosis type 1	DIS5A2M0	Strong	Biomarker	[1]
Azoospermia	DIS94181	Strong	Genetic Variation	[2]
Hypercalcaemia	DISKQ2K7	Strong	Genetic Variation	[3]
Male infertility	DISY3YZZ	Strong	Genetic Variation	[4]
Multiple sclerosis	DISB2WZI	Strong	Genetic Variation	[5]
Spermatogenic failure 77	DISI714L	Moderate	Autosomal recessive	[6]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Inactive peptidyl-prolyl cis-trans isomerase FKBP6 (FKBP6).	[7]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Inactive peptidyl-prolyl cis-trans isomerase FKBP6 (FKBP6).	[8]
Testosterone Undecanoate	DMZO10Y	Approved	Testosterone Undecanoate increases the expression of Inactive peptidyl-prolyl cis-trans isomerase FKBP6 (FKBP6).	[9]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Inactive peptidyl-prolyl cis-trans isomerase FKBP6 (FKBP6).	[10]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Inactive peptidyl-prolyl cis-trans isomerase FKBP6 (FKBP6).	[11]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Inactive peptidyl-prolyl cis-trans isomerase FKBP6 (FKBP6).	[12]

References

• [1] The role of immunophilins in mutant superoxide dismutase-1linked familial amyotrophic lateral sclerosis.Proc Natl Acad Sci U S A. 1999 Mar 16;96(6):3251-6. doi: 10.1073/pnas.96.6.3251.
• [2] Alterations in the steroid hormone receptor co-chaperone FKBPL are associated with male infertility: a case-control study.Reprod Biol Endocrinol. 2010 Mar 8;8:22. doi: 10.1186/1477-7827-8-22.
• [3] A novel human gene FKBP6 is deleted in Williams syndrome.Genomics. 1998 Sep 1;52(2):130-7. doi: 10.1006/geno.1998.5412.
• [4] Mutation screening of the FKBP6 gene and its association study with spermatogenic impairment in idiopathic infertile men.Reproduction. 2007 Feb;133(2):511-6. doi: 10.1530/REP-06-0125.
• [5] Linkage analysis and whole exome sequencing identify a novel candidate gene in a Dutch multiple sclerosis family.Mult Scler. 2019 Jun;25(7):909-917. doi: 10.1177/1352458518777202. Epub 2018 Jun 6.
• [6] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [7] 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.
• [8] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [9] Levonorgestrel enhances spermatogenesis suppression by testosterone with greater alteration in testicular gene expression in men. Biol Reprod. 2009 Mar;80(3):484-92.
• [10] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [11] Benzo[a]pyrene-induced changes in microRNA-mRNA networks. Chem Res Toxicol. 2012 Apr 16;25(4):838-49.
• [12] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.