Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT8RPSOC)

• DOT Name: Peptidyl-prolyl cis-trans isomerase FKBP8 (FKBP8)
• Synonyms: PPIase FKBP8; EC 5.2.1.8; 38 kDa FK506-binding protein; 38 kDa FKBP; FKBP-38; hFKBP38; FK506-binding protein 8; FKBP-8; FKBPR38; Rotamase
• Gene Name: FKBP8
• Related Disease:
  Amyotrophic lateral sclerosis type 1
  Clubfoot
  Hepatitis C virus infection
  Neural tube defect
• UniProt ID: FKBP8_HUMAN
• PDB ID: 2AWG; 2D9F; 2F2D; 2MF9; 3EY6; 5MGX
• EC Number: 5.2.1.8
• Pfam ID: PF00254 ; PF07719
• Sequence:
  MASCAEPSEPSAPLPAGVPPLEDFEVLDGVEDAEGEEEEEEEEEEEDDLSELPPLEDMGQ
  PPAEEAEQPGALAREFLAAMEPEPAPAPAPEEWLDILGNGLLRKKTLVPGPPGSSRPVKG
  QVVTVHLQTSLENGTRVQEEPELVFTLGDCDVIQALDLSVPLMDVGETAMVTADSKYCYG
  PQGRSPYIPPHAALCLEVTLKTAVDGPDLEMLTGQERVALANRKRECGNAHYQRADFVLA
  ANSYDLAIKAITSSAKVDMTFEEEAQLLQLKVKCLNNLAASQLKLDHYRAALRSCSLVLE
  HQPDNIKALFRKGKVLAQQGEYSEAIPILRAALKLEPSNKTIHAELSKLVKKHAAQRSTE
  TALYRKMLGNPSRLPAKCPGKGAWSIPWKWLFGATAVALGGVALSVVIAARN
• Function: Constitutively inactive PPiase, which becomes active when bound to calmodulin and calcium. Seems to act as a chaperone for BCL2, targets it to the mitochondria and modulates its phosphorylation state. The BCL2/FKBP8/calmodulin/calcium complex probably interferes with the binding of BCL2 to its targets. The active form of FKBP8 may therefore play a role in the regulation of apoptosis. Involved in the inhibition of viral infection by influenza A viruses (IAV).
• Tissue Specificity: Widely expressed. Highest levels seen in the brain. Highly abundant in the retina.
• KEGG Pathway: Mitophagy - animal (hsa04137)
• Reactome Pathway: Ub-specific processing proteases (R-HSA-5689880)

Molecular Interaction Atlas (MIA) of This DOT

4 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]
Clubfoot	DISLXT4S	Strong	Biomarker	[2]
Hepatitis C virus infection	DISQ0M8R	Strong	Biomarker	[3]
Neural tube defect	DIS5J95E	Disputed	Genetic Variation	[4]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Peptidyl-prolyl cis-trans isomerase FKBP8 (FKBP8).	[5]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Peptidyl-prolyl cis-trans isomerase FKBP8 (FKBP8).	[6]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Peptidyl-prolyl cis-trans isomerase FKBP8 (FKBP8).	[7]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Peptidyl-prolyl cis-trans isomerase FKBP8 (FKBP8).	[8]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Peptidyl-prolyl cis-trans isomerase FKBP8 (FKBP8).	[9]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Peptidyl-prolyl cis-trans isomerase FKBP8 (FKBP8).	[10]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of Peptidyl-prolyl cis-trans isomerase FKBP8 (FKBP8).	[5]
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate affects the expression of Peptidyl-prolyl cis-trans isomerase FKBP8 (FKBP8).	[11]
Clozapine	DMFC71L	Approved	Clozapine decreases the expression of Peptidyl-prolyl cis-trans isomerase FKBP8 (FKBP8).	[12]
Pioglitazone	DMKJ485	Approved	Pioglitazone increases the expression of Peptidyl-prolyl cis-trans isomerase FKBP8 (FKBP8).	[13]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Peptidyl-prolyl cis-trans isomerase FKBP8 (FKBP8).	[15]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Peptidyl-prolyl cis-trans isomerase FKBP8 (FKBP8).	[16]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A increases the expression of Peptidyl-prolyl cis-trans isomerase FKBP8 (FKBP8).	[17]
[3H]methyltrienolone	DMTSGOW	Investigative	[3H]methyltrienolone decreases the expression of Peptidyl-prolyl cis-trans isomerase FKBP8 (FKBP8).	[18]
all-trans-4-oxo-retinoic acid	DMM2R1N	Investigative	all-trans-4-oxo-retinoic acid increases the expression of Peptidyl-prolyl cis-trans isomerase FKBP8 (FKBP8).	[5]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
DNCB	DMDTVYC	Phase 2	DNCB affects the binding of Peptidyl-prolyl cis-trans isomerase FKBP8 (FKBP8).	[14]

References

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• [2] Regulation of apoptosis and neurite extension by FKBP38 is required for neural tube formation in the mouse.Genes Cells. 2008 Jun;13(6):635-51. doi: 10.1111/j.1365-2443.2008.01194.x. Epub 2008 May 4.
• [3] A single-amino-acid mutation in hepatitis C virus NS5A disrupts physical and functional interaction with the transcription factor HNF-1.J Gen Virol. 2015 Aug;96(8):2200-2205. doi: 10.1099/vir.0.000179. Epub 2015 May 8.
• [4] Mouse Fkbp8 activity is required to inhibit cell death and establish dorso-ventral patterning in the posterior neural tube.Hum Mol Genet. 2008 Feb 15;17(4):587-601. doi: 10.1093/hmg/ddm333. Epub 2007 Nov 13.
• [5] Retinoic acid and its 4-oxo metabolites are functionally active in human skin cells in vitro. J Invest Dermatol. 2005 Jul;125(1):143-53.
• [6] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [7] Gamma-irradiation and doxorubicin treatment of normal human cells cause cell cycle arrest via different pathways. Mol Cells. 2005 Dec 31;20(3):331-8.
• [8] 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.
• [9] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [10] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [11] Transcriptional profiling of testosterone-regulated genes in the skeletal muscle of human immunodeficiency virus-infected men experiencing weight loss. J Clin Endocrinol Metab. 2007 Jul;92(7):2793-802. doi: 10.1210/jc.2006-2722. Epub 2007 Apr 17.
• [12] Cannabidiol Displays Proteomic Similarities to Antipsychotics in Cuprizone-Exposed Human Oligodendrocytic Cell Line MO3.13. Front Mol Neurosci. 2021 May 28;14:673144. doi: 10.3389/fnmol.2021.673144. eCollection 2021.
• [13] Effects of metformin and pioglitazone combination on apoptosis and AMPK/mTOR signaling pathway in human anaplastic thyroid cancer cells. J Biochem Mol Toxicol. 2020 Oct;34(10):e22547. doi: 10.1002/jbt.22547. Epub 2020 Jun 26.
• [14] Proteomic analysis of the cellular response to a potent sensitiser unveils the dynamics of haptenation in living cells. Toxicology. 2020 Dec 1;445:152603. doi: 10.1016/j.tox.2020.152603. Epub 2020 Sep 28.
• [15] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.
• [16] Low-dose Bisphenol A exposure alters the functionality and cellular environment in a human cardiomyocyte model. Environ Pollut. 2023 Oct 15;335:122359. doi: 10.1016/j.envpol.2023.122359. Epub 2023 Aug 9.
• [17] Linking site-specific loss of histone acetylation to repression of gene expression by the mycotoxin ochratoxin A. Arch Toxicol. 2018 Feb;92(2):995-1014.
• [18] Evaluation of an in vitro model of androgen ablation and identification of the androgen responsive proteome in LNCaP cells. Proteomics. 2007 Jan;7(1):47-63.