Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT93D50X)

• DOT Name: F-box/LRR-repeat protein 5 (FBXL5)
• Synonyms: F-box and leucine-rich repeat protein 5; F-box protein FBL4/FBL5; p45SKP2-like protein
• Gene Name: FBXL5
• Related Disease:
  Acute lymphocytic leukaemia
  Cervical cancer
  Cervical carcinoma
  Childhood acute lymphoblastic leukemia
  Childhood myelodysplastic syndrome
  Colon cancer
  Colon carcinoma
  Gastric cancer
  Myelodysplastic syndrome
  Neuroblastoma
  Stomach cancer
  Hepatocellular carcinoma
• UniProt ID: FBXL5_HUMAN
• PDB ID: 3U9J; 3U9M; 3V5X; 3V5Y; 3V5Z; 6VCD
• Pfam ID: PF12937 ; PF01814 ; PF13516
• Sequence:
  MAPFPEEVDVFTAPHWRMKQLVGLYCDKLSKTNFSNNNDFRALLQSLYATFKEFKMHEQI
  ENEYIIGLLQQRSQTIYNVHSDNKLSEMLSLFEKGLKNVKNEYEQLNYAKQLKERLEAFT
  RDFLPHMKEEEEVFQPMLMEYFTYEELKDIKKKVIAQHCSQKDTAELLRGLSLWNHAEER
  QKFFKYSVDEKSDKEAEVSEHSTGITHLPPEVMLSIFSYLNPQELCRCSQVSMKWSQLTK
  TGSLWKHLYPVHWARGDWYSGPATELDTEPDDEWVKNRKDESRAFHEWDEDADIDESEES
  AEESIAISIAQMEKRLLHGLIHNVLPYVGTSVKTLVLAYSSAVSSKMVRQILELCPNLEH
  LDLTQTDISDSAFDSWSWLGCCQSLRHLDLSGCEKITDVALEKISRALGILTSHQSGFLK
  TSTSKITSTAWKNKDITMQSTKQYACLHDLTNKGIGEEIDNEHPWTKPVSSENFTSPYVW
  MLDAEDLADIEDTVEWRHRNVESLCVMETASNFSCSTSGCFSKDIVGLRTSVCWQQHCAS
  PAFAYCGHSFCCTGTALRTMSSLPESSAMCRKAARTRLPRGKDLIYFGSEKSDQETGRVL
  LFLSLSGCYQITDHGLRVLTLGGGLPYLEHLNLSGCLTITGAGLQDLVSACPSLNDEYFY
  YCDNINGPHADTASGCQNLQCGFRACCRSGE
• Function: Component of some SCF (SKP1-cullin-F-box) protein ligase complex that plays a central role in iron homeostasis by promoting the ubiquitination and subsequent degradation of IREB2/IRP2. The C-terminal domain of FBXL5 contains a redox-sensitive [2Fe-2S] cluster that, upon oxidation, promotes binding to IRP2 to effect its oxygen-dependent degradation. Under iron deficiency conditions, the N-terminal hemerythrin-like (Hr) region, which contains a diiron metal center, cannot bind iron and undergoes conformational changes that destabilize the FBXL5 protein and cause its ubiquitination and degradation. When intracellular iron levels start rising, the Hr region is stabilized. Additional increases in iron levels facilitate the assembly and incorporation of a redox active [2Fe-2S] cluster in the C-terminal domain. Only when oxygen level is high enough to maintain the cluster in its oxidized state can FBXL5 recruit IRP2 as a substrate for polyubiquination and degradation. Promotes ubiquitination and subsequent degradation of the dynactin complex component DCTN1. Within the nucleus, promotes the ubiquitination of SNAI1; preventing its interaction with DNA and promoting its degradation. Negatively regulates DNA damage response by mediating the ubiquitin-proteasome degradation of the DNA repair protein NABP2.
• Reactome Pathway:
  Neddylation (R-HSA-8951664)
  Iron uptake and transport (R-HSA-917937)
  Antigen processing (R-HSA-983168)
  Association of TriC/CCT with target proteins during biosynthesis (R-HSA-390471)

Molecular Interaction Atlas (MIA) of This DOT

12 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute lymphocytic leukaemia	DISPX75S	Strong	Biomarker	[1]
Cervical cancer	DISFSHPF	Strong	Biomarker	[2]
Cervical carcinoma	DIST4S00	Strong	Biomarker	[2]
Childhood acute lymphoblastic leukemia	DISJ5D6U	Strong	Biomarker	[1]
Childhood myelodysplastic syndrome	DISMN80I	Strong	Altered Expression	[3]
Colon cancer	DISVC52G	Strong	Biomarker	[2]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[2]
Gastric cancer	DISXGOUK	Strong	Biomarker	[2]
Myelodysplastic syndrome	DISYHNUI	Strong	Altered Expression	[3]
Neuroblastoma	DISVZBI4	Strong	Biomarker	[4]
Stomach cancer	DISKIJSX	Strong	Biomarker	[2]
Hepatocellular carcinoma	DIS0J828	Limited	Biomarker	[5]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of F-box/LRR-repeat protein 5 (FBXL5).	[6]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of F-box/LRR-repeat protein 5 (FBXL5).	[7]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of F-box/LRR-repeat protein 5 (FBXL5).	[8]
Arsenic	DMTL2Y1	Approved	Arsenic affects the expression of F-box/LRR-repeat protein 5 (FBXL5).	[9]
Selenium	DM25CGV	Approved	Selenium decreases the expression of F-box/LRR-repeat protein 5 (FBXL5).	[10]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of F-box/LRR-repeat protein 5 (FBXL5).	[11]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of F-box/LRR-repeat protein 5 (FBXL5).	[12]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of F-box/LRR-repeat protein 5 (FBXL5).	[13]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of F-box/LRR-repeat protein 5 (FBXL5).	[14]

References

• [1] Identification of promising prognostic genes for relapsed acute lymphoblastic leukemia.Blood Cells Mol Dis. 2019 Jul;77:113-119. doi: 10.1016/j.bcmd.2019.04.010. Epub 2019 Apr 18.
• [2] F-box and leucine-rich repeat protein 5 promotes colon cancer progression by modulating PTEN/PI3K/AKT signaling pathway.Biomed Pharmacother. 2018 Nov;107:1712-1719. doi: 10.1016/j.biopha.2018.08.119. Epub 2018 Sep 8.
• [3] Essential role of FBXL5-mediated cellular iron homeostasis in maintenance of hematopoietic stem cells.Nat Commun. 2017 Jul 17;8:16114. doi: 10.1038/ncomms16114.
• [4] Oxidative Stress Regulated Iron Regulatory Protein IRP2 Through FBXL5-Mediated Ubiquitination-Proteasome Way in SH-SY5Y Cells.Front Neurosci. 2019 Jan 29;13:20. doi: 10.3389/fnins.2019.00020. eCollection 2019.
• [5] Disruption of FBXL5-mediated cellular iron homeostasis promotes liver carcinogenesis.J Exp Med. 2019 Apr 1;216(4):950-965. doi: 10.1084/jem.20180900. Epub 2019 Mar 15.
• [6] 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.
• [7] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [8] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [9] Drinking-water arsenic exposure modulates gene expression in human lymphocytes from a U.S. population. Environ Health Perspect. 2008 Apr;116(4):524-31. doi: 10.1289/ehp.10861.
• [10] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [11] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [12] 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.
• [13] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.
• [14] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.