Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT8CMPB2)

• DOT Name: Peptidyl-prolyl cis-trans isomerase FKBP1B (FKBP1B)
• Synonyms: PPIase FKBP1B; EC 5.2.1.8; 12.6 kDa FK506-binding protein; 12.6 kDa FKBP; FKBP-12.6; FK506-binding protein 1B; FKBP-1B; Immunophilin FKBP12.6; Rotamase; h-FKBP-12
• Gene Name: FKBP1B
• Related Disease:
  Cardiac failure
  Congestive heart failure
  Abscess
  Amyotrophic lateral sclerosis type 1
  Arrhythmia
  Autoimmune disease
  Cardiomyopathy
  Catecholaminergic polymorphic ventricular tachycardia 1
  Essential hypertension
  Gastric disease
  Idiopathic cardiomyopathy
  Parkinson disease
  Ventricular tachycardia
  Ventricular fibrillation
• UniProt ID: FKB1B_HUMAN
• PDB ID: 1C9H ; 4C02 ; 4IQ2 ; 4IQC ; 5HKG ; 5L1D ; 5T15 ; 5T9M ; 5T9N ; 5T9R ; 5T9S ; 5T9V ; 5TA3 ; 5TAL ; 5TAM ; 5TAN ; 5TAP ; 5TAQ ; 5TAS ; 5TAT ; 5TAU ; 5TAV ; 5TAW ; 5TAX ; 5TAY ; 5TAZ ; 5TB0 ; 5TB1 ; 5TB2 ; 5TB3 ; 5TB4 ; 6JGZ ; 6JH6 ; 6JHN ; 6JI0 ; 6JI8 ; 6JII ; 6JIU ; 6JIY ; 6JRR ; 6JRS ; 6M2W ; 6PV6 ; 6W1N ; 6WOT ; 6WOU ; 6WOV ; 6X32 ; 6X33 ; 6X34 ; 6X35 ; 6X36 ; 7CF9 ; 7JMF ; 7JMG ; 7JMH ; 7JMI ; 7JMJ ; 7M6A ; 7M6L ; 7T64 ; 7T65 ; 7U9Q ; 7U9R ; 7U9T ; 7U9X ; 7U9Z ; 7UA1 ; 7UA3 ; 7UA4 ; 7UA5 ; 7UA9 ; 7VML ; 7VMM ; 7VMN ; 7VMO ; 7VMP ; 7VMQ ; 7VMR ; 7VMS ; 8DUJ ; 8DVE ; 8SEN ; 8SEO ; 8SEP ; 8SEQ ; 8SER ; 8SES ; 8SET ; 8UQ2 ; 8UQ3 ; 8UQ4 ; 8UXC ; 8UXE ; 8UXF ; 8UXG ; 8UXH ; 8UXI ; 8UXL ; 8UXM
• EC Number: 5.2.1.8
• Pfam ID: PF00254
• Sequence:
  MGVEIETISPGDGRTFPKKGQTCVVHYTGMLQNGKKFDSSRDRNKPFKFRIGKQEVIKGF
  EEGAAQMSLGQRAKLTCTPDVAYGATGHPGVIPPNATLIFDVELLNLE
• Function: Has the potential to contribute to the immunosuppressive and toxic effects of FK506 and rapamycin. PPIases accelerate the folding of proteins. It catalyzes the cis-trans isomerization of proline imidic peptide bonds in oligopeptides.
• Tissue Specificity: Detected in heart muscle (at protein level). Isoform 1 and isoform 2 are ubiquitous with highest levels in brain and thymus.
• Reactome Pathway:
  Ion homeostasis (R-HSA-5578775)
  Stimuli-sensing channels (R-HSA-2672351)

Molecular Interaction Atlas (MIA) of This DOT

14 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cardiac failure	DISDC067	Definitive	Biomarker	[1]
Congestive heart failure	DIS32MEA	Definitive	Biomarker	[1]
Abscess	DISAP982	Strong	Biomarker	[2]
Amyotrophic lateral sclerosis type 1	DIS5A2M0	Strong	Biomarker	[3]
Arrhythmia	DISFF2NI	Strong	Biomarker	[4]
Autoimmune disease	DISORMTM	Strong	Biomarker	[5]
Cardiomyopathy	DISUPZRG	Strong	Biomarker	[6]
Catecholaminergic polymorphic ventricular tachycardia 1	DISKGB3F	Strong	Genetic Variation	[7]
Essential hypertension	DIS7WI98	Strong	Genetic Variation	[8]
Gastric disease	DISNZNTG	Strong	Biomarker	[9]
Idiopathic cardiomyopathy	DISUGBZL	Strong	Biomarker	[6]
Parkinson disease	DISQVHKL	Strong	Biomarker	[10]
Ventricular tachycardia	DISIBXJ3	Strong	Biomarker	[7]
Ventricular fibrillation	DIS7IN76	Limited	Biomarker	[11]

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Fluorouracil	DMUM7HZ	Approved	Peptidyl-prolyl cis-trans isomerase FKBP1B (FKBP1B) affects the response to substance of Fluorouracil.	[24]
Cyclophosphamide	DM4O2Z7	Approved	Peptidyl-prolyl cis-trans isomerase FKBP1B (FKBP1B) affects the response to substance of Cyclophosphamide.	[24]

12 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 Peptidyl-prolyl cis-trans isomerase FKBP1B (FKBP1B).	[12]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Peptidyl-prolyl cis-trans isomerase FKBP1B (FKBP1B).	[13]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Peptidyl-prolyl cis-trans isomerase FKBP1B (FKBP1B).	[14]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Peptidyl-prolyl cis-trans isomerase FKBP1B (FKBP1B).	[15]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Peptidyl-prolyl cis-trans isomerase FKBP1B (FKBP1B).	[16]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Peptidyl-prolyl cis-trans isomerase FKBP1B (FKBP1B).	[17]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Peptidyl-prolyl cis-trans isomerase FKBP1B (FKBP1B).	[17]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Peptidyl-prolyl cis-trans isomerase FKBP1B (FKBP1B).	[18]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Peptidyl-prolyl cis-trans isomerase FKBP1B (FKBP1B).	[19]
Seocalcitol	DMKL9QO	Phase 3	Seocalcitol increases the expression of Peptidyl-prolyl cis-trans isomerase FKBP1B (FKBP1B).	[20]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Peptidyl-prolyl cis-trans isomerase FKBP1B (FKBP1B).	[22]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Peptidyl-prolyl cis-trans isomerase FKBP1B (FKBP1B).	[23]

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 Peptidyl-prolyl cis-trans isomerase FKBP1B (FKBP1B).	[21]

References

• [1] Down-regulation of FKBP12.6 and SERCA2a contributes to acute heart failure in septic shock and is related to an up-regulated endothelin signalling pathway.J Pharm Pharmacol. 2007 Jul;59(7):977-84. doi: 10.1211/jpp.59.7.0010.
• [2] Novel Regulation of Alpha-Toxin and the Phenol-Soluble Modulins by Peptidyl-Prolyl cis/trans Isomerase Enzymes in Staphylococcus aureus.Toxins (Basel). 2019 Jun 16;11(6):343. doi: 10.3390/toxins11060343.
• [3] 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.
• [4] Decreased FKBP12.6 expression and enhanced endothelin receptor signaling associated with arrhymogenesis in myocardial infarction rats.Phytother Res. 2008 Aug;22(8):1115-24. doi: 10.1002/ptr.2470.
• [5] Evidence of association between FKBP1B and thyroid autoimmune disorders in a large Tunisian family.Autoimmunity. 2004 May;37(3):237-9. doi: 10.1080/08916930410001702478.
• [6] Total triterpene acids, active ingredients from Fructus Corni, attenuate diabetic cardiomyopathy by normalizing ET pathway and expression of FKBP12.6 and SERCA2a in streptozotocin-rats.J Pharm Pharmacol. 2008 Dec;60(12):1687-94. doi: 10.1211/jpp/60.12.0016.
• [7] Stabilization of cardiac ryanodine receptor prevents intracellular calcium leak and arrhythmias.Proc Natl Acad Sci U S A. 2006 May 16;103(20):7906-10. doi: 10.1073/pnas.0602133103. Epub 2006 May 3.
• [8] Association of EDNRA, but not WNK4 or FKBP1B, polymorphisms with essential hypertension.Clin Genet. 2003 Nov;64(5):433-8. doi: 10.1034/j.1399-0004.2003.00148.x.
• [9] Differential Proteomic Analysis Reveals Protein Networks and Pathways that May Contribute to Helicobacter pylori FKBP-Type PPIase-Associated Gastric Diseases.Proteomics Clin Appl. 2018 May;12(3):e1700127. doi: 10.1002/prca.201700127. Epub 2017 Dec 5.
• [10] The Molecular Basis of the Interaction of CyclophilinA with -Synuclein.Angew Chem Int Ed Engl. 2020 Mar 27;59(14):5643-5646. doi: 10.1002/anie.201914878. Epub 2020 Jan 29.
• [11] Abrupt changes in FKBP12.6 and SERCA2a expression contribute to sudden occurrence of ventricular fibrillation on reperfusion and are prevented by CPU86017.Acta Pharmacol Sin. 2007 Jun;28(6):773-82. doi: 10.1111/j.1745-7254.2007.00580.x.
• [12] The neuroprotective action of the mood stabilizing drugs lithium chloride and sodium valproate is mediated through the up-regulation of the homeodomain protein Six1. Toxicol Appl Pharmacol. 2009 Feb 15;235(1):124-34.
• [13] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [14] 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.
• [15] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [16] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [17] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [18] Epigenetic silencing of novel tumor suppressors in malignant melanoma. Cancer Res. 2006 Dec 1;66(23):11187-93. doi: 10.1158/0008-5472.CAN-06-1274.
• [19] LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
• [20] Expression profiling in squamous carcinoma cells reveals pleiotropic effects of vitamin D3 analog EB1089 signaling on cell proliferation, differentiation, and immune system regulation. Mol Endocrinol. 2002 Jun;16(6):1243-56.
• [21] 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.
• [22] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [23] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.
• [24] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.