Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTVK43OK)

• DOT Name: FAD-linked sulfhydryl oxidase ALR (GFER)
• Synonyms: EC 1.8.3.2; Augmenter of liver regeneration; hERV1; Hepatopoietin
• Gene Name: GFER
• Related Disease:
  Acute lymphocytic leukaemia
  Lung cancer
  Lung carcinoma
  Lymphoid leukemia
  T-cell acute lymphoblastic leukaemia
  Acute liver failure
  Alzheimer disease
  Anorexia nervosa cachexia
  Arteriosclerosis
  Arthritis
  Atherosclerosis
  Autoimmune disease
  Cholangiocarcinoma
  Classic Hodgkin lymphoma
  Colon cancer
  Colon carcinoma
  Congenital cataract-progressive muscular hypotonia-hearing loss-developmental delay syndrome
  Diabetic retinopathy
  Epilepsy
  Hepatitis B virus infection
  Hepatitis C virus infection
  Hepatocellular carcinoma
  Liver failure
  Major depressive disorder
  Neoplasm
  Non-insulin dependent diabetes
  Obesity
  Plasma cell myeloma
  Pulmonary disease
  Sensorineural hearing loss disorder
  Type-1/2 diabetes
  Liver cirrhosis
  Acute kidney injury
  Advanced cancer
  Ankylosing spondylitis
  Bone osteosarcoma
  Cardiomyopathy
  Cryptorchidism
  Eosinophilic esophagitis
  Fatty liver disease
  Hyperglycemia
  Intellectual disability
  Mitochondrial disease
  Myopathy
  Osteosarcoma
  Peripheral neuropathy
  Type-1 diabetes
• UniProt ID: ALR_HUMAN
• PDB ID: 3MBG; 3O55; 3TK0; 3U2L; 3U2M; 3U5S; 4LDK
• EC Number: 1.8.3.2
• Pfam ID: PF04777
• Sequence:
  MAAPGERGRFHGGNLFFLPGGARSEMMDDLATDARGRGAGRRDAAASASTPAQAPTSDSP
  VAEDASRRRPCRACVDFKTWMRTQQKRDTKFREDCPPDREELGRHSWAVLHTLAAYYPDL
  PTPEQQQDMAQFIHLFSKFYPCEECAEDLRKRLCRNHPDTRTRACFTQWLCHLHNEVNRK
  LGKPDFDCSKVDERWRDGWKDGSCD
• Function: [Isoform 1]: FAD-dependent sulfhydryl oxidase that regenerates the redox-active disulfide bonds in CHCHD4/MIA40, a chaperone essential for disulfide bond formation and protein folding in the mitochondrial intermembrane space. The reduced form of CHCHD4/MIA40 forms a transient intermolecular disulfide bridge with GFER/ERV1, resulting in regeneration of the essential disulfide bonds in CHCHD4/MIA40, while GFER/ERV1 becomes re-oxidized by donating electrons to cytochrome c or molecular oxygen; [Isoform 2]: May act as an autocrine hepatotrophic growth factor promoting liver regeneration.
• Tissue Specificity: Ubiquitously expressed. Highest expression in the testis and liver and low expression in the muscle.
• Reactome Pathway: Mitochondrial protein import (R-HSA-1268020)

Molecular Interaction Atlas (MIA) of This DOT

47 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute lymphocytic leukaemia	DISPX75S	Definitive	Altered Expression	[1]
Lung cancer	DISCM4YA	Definitive	Biomarker	[2]
Lung carcinoma	DISTR26C	Definitive	Biomarker	[2]
Lymphoid leukemia	DIS65TYQ	Definitive	Altered Expression	[1]
T-cell acute lymphoblastic leukaemia	DIS17AI2	Definitive	Biomarker	[1]
Acute liver failure	DIS5EZKX	Strong	Altered Expression	[3]
Alzheimer disease	DISF8S70	Strong	Biomarker	[4]
Anorexia nervosa cachexia	DISFO5RQ	Strong	Altered Expression	[5]
Arteriosclerosis	DISK5QGC	Strong	Biomarker	[6]
Arthritis	DIST1YEL	Strong	Biomarker	[7]
Atherosclerosis	DISMN9J3	Strong	Biomarker	[6]
Autoimmune disease	DISORMTM	Strong	Genetic Variation	[8]
Cholangiocarcinoma	DIS71F6X	Strong	Altered Expression	[9]
Classic Hodgkin lymphoma	DISV1LU6	Strong	Biomarker	[10]
Colon cancer	DISVC52G	Strong	Altered Expression	[11]
Colon carcinoma	DISJYKUO	Strong	Altered Expression	[11]
Congenital cataract-progressive muscular hypotonia-hearing loss-developmental delay syndrome	DISWYU8M	Strong	Autosomal recessive	[12]
Diabetic retinopathy	DISHGUJM	Strong	Genetic Variation	[13]
Epilepsy	DISBB28L	Strong	Biomarker	[14]
Hepatitis B virus infection	DISLQ2XY	Strong	Altered Expression	[15]
Hepatitis C virus infection	DISQ0M8R	Strong	Altered Expression	[15]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[16]
Liver failure	DISLGEL6	Strong	Biomarker	[16]
Major depressive disorder	DIS4CL3X	Strong	Biomarker	[17]
Neoplasm	DISZKGEW	Strong	Biomarker	[18]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Biomarker	[19]
Obesity	DIS47Y1K	Strong	Biomarker	[19]
Plasma cell myeloma	DIS0DFZ0	Strong	Altered Expression	[20]
Pulmonary disease	DIS6060I	Strong	Biomarker	[7]
Sensorineural hearing loss disorder	DISJV45Z	Strong	Biomarker	[21]
Type-1/2 diabetes	DISIUHAP	Strong	Altered Expression	[19]
Liver cirrhosis	DIS4G1GX	moderate	Altered Expression	[3]
Acute kidney injury	DISXZG0T	Disputed	Therapeutic	[22]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[23]
Ankylosing spondylitis	DISRC6IR	Limited	Biomarker	[24]
Bone osteosarcoma	DIST1004	Limited	Biomarker	[25]
Cardiomyopathy	DISUPZRG	Limited	Biomarker	[26]
Cryptorchidism	DISYUD2P	Limited	Biomarker	[27]
Eosinophilic esophagitis	DISR8WSB	Limited	Biomarker	[28]
Fatty liver disease	DIS485QZ	Limited	Biomarker	[29]
Hyperglycemia	DIS0BZB5	Limited	Biomarker	[30]
Intellectual disability	DISMBNXP	Limited	Biomarker	[31]
Mitochondrial disease	DISKAHA3	Limited	CausalMutation	[32]
Myopathy	DISOWG27	Limited	Genetic Variation	[33]
Osteosarcoma	DISLQ7E2	Limited	Biomarker	[25]
Peripheral neuropathy	DIS7KN5G	Limited	Genetic Variation	[34]
Type-1 diabetes	DIS7HLUB	Limited	Biomarker	[35]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Hydrogen peroxide	DM1NG5W	Approved	FAD-linked sulfhydryl oxidase ALR (GFER) affects the response to substance of Hydrogen peroxide.	[46]

3 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 FAD-linked sulfhydryl oxidase ALR (GFER).	[36]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of FAD-linked sulfhydryl oxidase ALR (GFER).	[43]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of FAD-linked sulfhydryl oxidase ALR (GFER).	[45]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of FAD-linked sulfhydryl oxidase ALR (GFER).	[37]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of FAD-linked sulfhydryl oxidase ALR (GFER).	[38]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of FAD-linked sulfhydryl oxidase ALR (GFER).	[39]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of FAD-linked sulfhydryl oxidase ALR (GFER).	[40]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of FAD-linked sulfhydryl oxidase ALR (GFER).	[41]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of FAD-linked sulfhydryl oxidase ALR (GFER).	[42]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of FAD-linked sulfhydryl oxidase ALR (GFER).	[44]

References

• [1] Decreased expression of the augmenter of liver regeneration results in growth inhibition and increased chemosensitivity of acute T lymphoblastic leukemia cells.Oncol Rep. 2017 Nov;38(5):3130-3136. doi: 10.3892/or.2017.5984. Epub 2017 Sep 21.
• [2] Induction of Human-Lung-Cancer-A549-Cell Apoptosis by 4-Hydroperoxy-2-decenoic Acid Ethyl Ester through Intracellular ROS Accumulation and the Induction of Proapoptotic CHOP Expression.J Agric Food Chem. 2018 Oct 17;66(41):10741-10747. doi: 10.1021/acs.jafc.8b04424. Epub 2018 Oct 8.
• [3] Augmenter of liver regeneration protects against carbon tetrachloride-induced liver injury by promoting autophagy in mice.Oncotarget. 2017 Feb 21;8(8):12637-12648. doi: 10.18632/oncotarget.14478.
• [4] Optimized turmeric extract reduces -Amyloid and phosphorylated Tau protein burden in Alzheimer's transgenic mice.Curr Alzheimer Res. 2012 May;9(4):500-6. doi: 10.2174/156720512800492459.
• [5] Time course of adiponectin and its relationship to psychological aspects in patients with anorexia nervosa during inpatient treatment.PLoS One. 2017 Dec 20;12(12):e0189500. doi: 10.1371/journal.pone.0189500. eCollection 2017.
• [6] ERV1/ChemR23 Signaling Protects Against Atherosclerosis by Modifying Oxidized Low-Density Lipoprotein Uptake and Phagocytosis in Macrophages.Circulation. 2018 Oct 16;138(16):1693-1705. doi: 10.1161/CIRCULATIONAHA.117.032801.
• [7] The musculoskeletal manifestations of cystic fibrosis.Semin Arthritis Rheum. 1986 Feb;15(3):213-25. doi: 10.1016/0049-0172(86)90018-1.
• [8] AIM2-Like Receptors Positively and Negatively Regulate the Interferon Response Induced by Cytosolic DNA.mBio. 2017 Jul 5;8(4):e00944-17. doi: 10.1128/mBio.00944-17.
• [9] Expression of augmenter of liver regeneration (ALR) in human liver cirrhosis and carcinoma.Histopathology. 2005 Jul;47(1):57-66. doi: 10.1111/j.1365-2559.2005.02172.x.
• [10] Rare disease knowledge enrichment through a data-driven approach.BMC Med Inform Decis Mak. 2019 Feb 14;19(1):32. doi: 10.1186/s12911-019-0752-9.
• [11] Augmenter of liver regeneration gene expression in human colon cancer cell lines and clinical tissue samples.J BUON. 2015 Jan-Feb;20(1):84-91.
• [12] The mitochondrial disulfide relay system protein GFER is mutated in autosomal-recessive myopathy with cataract and combined respiratory-chain deficiency. Am J Hum Genet. 2009 May;84(5):594-604. doi: 10.1016/j.ajhg.2009.04.004. Epub 2009 Apr 30.
• [13] Meta-analysis of the association between aldose reductase gene (CA)n microsatellite variants and risk of diabetic retinopathy.Exp Ther Med. 2019 Dec;18(6):4499-4509. doi: 10.3892/etm.2019.8086. Epub 2019 Oct 8.
• [14] HPO-Shuffle: an associated gene prioritization strategy and its application in drug repurposing for the treatment of canine epilepsy.Biosci Rep. 2019 Sep 6;39(9):BSR20191247. doi: 10.1042/BSR20191247. Print 2019 Sep 30.
• [15] Nrf2 activates augmenter of liver regeneration (ALR) via antioxidant response element and links oxidative stress to liver regeneration.Mol Med. 2013 Aug 28;19(1):237-44. doi: 10.2119/molmed.2013.00027.
• [16] Augmenter of liver regeneration: A key protein in liver regeneration and pathophysiology.Hepatol Res. 2018 Jul;48(8):587-596. doi: 10.1111/hepr.13077. Epub 2018 May 14.
• [17] The Influence of Depression on the Psychometric Properties of the Maslach Burnout Inventory-Human Services Survey: A Cross-Sectional Study With Nursing Assistants.Front Psychiatry. 2018 Dec 18;9:695. doi: 10.3389/fpsyt.2018.00695. eCollection 2018.
• [18] Clinical Implications of Augmenter of Liver Regeneration in Cancer: A Systematic Review.Anticancer Res. 2017 Jul;37(7):3379-3383. doi: 10.21873/anticanres.11704.
• [19] Type 2 diabetes and metabolic syndrome - adipokine levels and effect of drugs.Gynecol Endocrinol. 2017 Jan;33(1):75-78. doi: 10.1080/09513590.2016.1207165. Epub 2016 Oct 5.
• [20] Silencing of augmenter of liver regeneration inhibited cell proliferation and triggered apoptosis in U266 human multiple myeloma cells.Braz J Med Biol Res. 2017 Aug 31;50(10):e6139. doi: 10.1590/1414-431X20176139.
• [21] Polygenic inheritance of sensorineural hearing loss (Snhl2, -3, and -4) and organ of Corti patterning defect in the ALR/LtJ mouse strain.Hear Res. 2011 May;275(1-2):150-9. doi: 10.1016/j.heares.2010.12.017. Epub 2010 Dec 24.
• [22] Expression of augmenter of liver regeneration in rats with gentamicin-induced acute renal failure and its protective effect on kidney.Ren Fail. 2009;31(10):946-55. doi: 10.3109/08860220903216154.
• [23] Measuring Burnout in Pediatric Oncology Staff: Should We Be Using the Maslach Burnout Inventory?.J Pediatr Oncol Nurs. 2020 Jan/Feb;37(1):55-64. doi: 10.1177/1043454219873638. Epub 2019 Sep 17.
• [24] Simplified Chinese version of hip and knee replacement expectations surveys in patients with osteoarthritis and ankylosing spondylitis: cross-cultural adaptation, validation and reliability.BMC Musculoskelet Disord. 2018 Jul 21;19(1):247. doi: 10.1186/s12891-018-2129-0.
• [25] Analysis of the Expression of Repetitive DNA Elements in Osteosarcoma.Front Genet. 2017 Nov 30;8:193. doi: 10.3389/fgene.2017.00193. eCollection 2017.
• [26] Impact of Compound Hypertonic Saline Solution on Decompensated Heart Failure.Int Heart J. 2017 Aug 3;58(4):601-607. doi: 10.1536/ihj.16-313. Epub 2017 Jul 13.
• [27] [Expression of augmenter of liver regeneration in cryptorchidism spermatogenic cells and its implication].Zhonghua Nan Ke Xue. 2007 Aug;13(8):700-5.
• [28] Budesonide Oral Suspension Significantly Improves Eosinophilic Esophagitis Histology Scoring System Results: Analyses From a 12-Week, Phase 2, Randomized, Placebo-controlled Trial.Am J Surg Pathol. 2019 Nov;43(11):1501-1509. doi: 10.1097/PAS.0000000000001361.
• [29] Augmenter of liver regeneration protein deficiency promotes hepatic steatosis by inducing oxidative stress and microRNA-540 expression.FASEB J. 2019 Mar;33(3):3825-3840. doi: 10.1096/fj.201802015R. Epub 2018 Dec 12.
• [30] ERV1 Overexpression in Myeloid Cells Protects against High Fat Diet Induced Obesity and Glucose Intolerance.Sci Rep. 2017 Oct 9;7(1):12848. doi: 10.1038/s41598-017-13185-7.
• [31] Further delineation of a rare recessive encephalomyopathy linked to mutations in GFER thanks to data sharing of whole exome sequencing data.Clin Genet. 2017 Aug;92(2):188-198. doi: 10.1111/cge.12985. Epub 2017 Mar 1.
• [32] Decreased male reproductive success in association with mitochondrial dysfunction.Eur J Hum Genet. 2017 Oct;25(10):1162-1164. doi: 10.1038/ejhg.2017.114. Epub 2017 Aug 16.
• [33] The disease-associated mutation of the mitochondrial thiol oxidase Erv1 impairs cofactor binding during its catalytic reaction.Biochem J. 2014 Dec 15;464(3):449-59. doi: 10.1042/BJ20140679.
• [34] Association of aldose reductase gene polymorphism (C-106T) in susceptibility of diabetic peripheral neuropathy among north Indian population.J Diabetes Complications. 2017 Jul;31(7):1085-1089. doi: 10.1016/j.jdiacomp.2017.04.011. Epub 2017 Apr 28.
• [35] Role of increased ROS dissipation in prevention of T1D.Ann N Y Acad Sci. 2008 Dec;1150:157-66. doi: 10.1196/annals.1447.045.
• [36] 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.
• [37] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [38] Increased mitochondrial ROS formation by acetaminophen in human hepatic cells is associated with gene expression changes suggesting disruption of the mitochondrial electron transport chain. Toxicol Lett. 2015 Apr 16;234(2):139-50.
• [39] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [40] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [41] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [42] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [43] 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.
• [44] 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.
• [45] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [46] [Transfection of human hepatic stimulator substance gene could protect BEL-7402 cells against hepatotoxins]. Zhonghua Gan Zang Bing Za Zhi. 2004 Feb;12(2):99-101.