Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTLCYA32)

• DOT Name: Glucose-6-phosphate exchanger SLC37A4 (SLC37A4)
• Synonyms: Glucose-5-phosphate transporter; Glucose-6-phosphate translocase; Solute carrier family 37 member 4; Transformation-related gene 19 protein; TRG-19
• Gene Name: SLC37A4
• Related Disease:
  Glycogen storage disease Ib
  Glycogen storage disease type 1 due to SLC37A4 mutation
  Congenital disorder of glycosylation, type IIw
• UniProt ID: G6PT1_HUMAN
• Pfam ID: PF07690
• Sequence:
  MAAQGYGYYRTVIFSAMFGGYSLYYFNRKTFSFVMPSLVEEIPLDKDDLGFITSSQSAAY
  AISKFVSGVLSDQMSARWLFSSGLLLVGLVNIFFAWSSTVPVFAALWFLNGLAQGLGWPP
  CGKVLRKWFEPSQFGTWWAILSTSMNLAGGLGPILATILAQSYSWRSTLALSGALCVVVS
  FLCLLLIHNEPADVGLRNLDPMPSEGKKGSLKEESTLQELLLSPYLWVLSTGYLVVFGVK
  TCCTDWGQFFLIQEKGQSALVGSSYMSALEVGGLVGSIAAGYLSDRAMAKAGLSNYGNPR
  HGLLLFMMAGMTVSMYLFRVTVTSDSPKLWILVLGAVFGFSSYGPIALFGVIANESAPPN
  LCGTSHAIVGLMANVGGFLAGLPFSTIAKHYSWSTAFWVAEVICAASTAAFFLLRNIRTK
  MGRVSKKAE
• Function: Inorganic phosphate and glucose-6-phosphate antiporter of the endoplasmic reticulum. Transports cytoplasmic glucose-6-phosphate into the lumen of the endoplasmic reticulum and translocates inorganic phosphate into the opposite direction. Forms with glucose-6-phosphatase the complex responsible for glucose production through glycogenolysis and gluconeogenesis. Hence, it plays a central role in homeostatic regulation of blood glucose levels.
• Tissue Specificity: Mostly expressed in liver and kidney.
• KEGG Pathway: Carbohydrate digestion and absorption (hsa04973)
• Reactome Pathway:
  Gluconeogenesis (R-HSA-70263)
  Glycogen storage disease type Ib (SLC37A4) (R-HSA-3229133)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Glycogen storage disease Ib	DIS2SL6J	Definitive	Autosomal recessive	[1]
Glycogen storage disease type 1 due to SLC37A4 mutation	DISA9APD	Definitive	Autosomal recessive	[2]
Congenital disorder of glycosylation, type IIw	DISP0QHJ	Strong	Autosomal dominant	[3]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Glucose-6-phosphate exchanger SLC37A4 (SLC37A4).	[4]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Glucose-6-phosphate exchanger SLC37A4 (SLC37A4).	[5]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Glucose-6-phosphate exchanger SLC37A4 (SLC37A4).	[6]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Glucose-6-phosphate exchanger SLC37A4 (SLC37A4).	[7]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Glucose-6-phosphate exchanger SLC37A4 (SLC37A4).	[8]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Glucose-6-phosphate exchanger SLC37A4 (SLC37A4).	[9]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Glucose-6-phosphate exchanger SLC37A4 (SLC37A4).	[5]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Glucose-6-phosphate exchanger SLC37A4 (SLC37A4).	[10]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Glucose-6-phosphate exchanger SLC37A4 (SLC37A4).	[11]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Glucose-6-phosphate exchanger SLC37A4 (SLC37A4).	[12]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Glucose-6-phosphate exchanger SLC37A4 (SLC37A4).	[13]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Glucose-6-phosphate exchanger SLC37A4 (SLC37A4).	[14]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of Glucose-6-phosphate exchanger SLC37A4 (SLC37A4).	[15]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone decreases the expression of Glucose-6-phosphate exchanger SLC37A4 (SLC37A4).	[16]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Glucose-6-phosphate exchanger SLC37A4 (SLC37A4).	[17]
Curcumin	DMQPH29	Phase 3	Curcumin decreases the expression of Glucose-6-phosphate exchanger SLC37A4 (SLC37A4).	[18]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Glucose-6-phosphate exchanger SLC37A4 (SLC37A4).	[5]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Glucose-6-phosphate exchanger SLC37A4 (SLC37A4).	[19]

References

• [1] Determining mutations in G6PC and SLC37A4 genes in a sample of Brazilian patients with glycogen storage disease types Ia and Ib. Genet Mol Biol. 2013 Dec;36(4):502-6. doi: 10.1590/S1415-47572013000400007. Epub 2013 Nov 8.
• [2] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [3] SLC37A4-CDG: Mislocalization of the glucose-6-phosphate transporter to the Golgi causes a new congenital disorder of glycosylation. Mol Genet Metab Rep. 2020 Aug 21;25:100636. doi: 10.1016/j.ymgmr.2020.100636. eCollection 2020 Dec.
• [4] 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.
• [5] 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.
• [6] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [7] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [8] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [9] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [10] 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.
• [11] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [12] Arsenic trioxide induces differentiation of cancer stem cells in hepatocellular carcinoma through inhibition of LIF/JAK1/STAT3 and NF-kB signaling pathways synergistically. Clin Transl Med. 2021 Feb;11(2):e335. doi: 10.1002/ctm2.335.
• [13] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [14] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [15] G6PC2 Modulates Fasting Blood Glucose In Male Mice in Response to Stress. Endocrinology. 2016 Aug;157(8):3002-8. doi: 10.1210/en.2016-1245. Epub 2016 Jun 14.
• [16] Transcriptomic analysis of untreated and drug-treated differentiated HepaRG cells over a 2-week period. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):27-35.
• [17] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [18] Silencing of the human microsomal glucose-6-phosphate translocase induces glioma cell death: potential new anticancer target for curcumin. FEBS Lett. 2006 Jun 26;580(15):3746-52. doi: 10.1016/j.febslet.2006.05.071. Epub 2006 Jun 9.
• [19] Comprehensive analysis of transcriptomic changes induced by low and high doses of bisphenol A in HepG2 spheroids in vitro and rat liver in vivo. Environ Res. 2019 Jun;173:124-134. doi: 10.1016/j.envres.2019.03.035. Epub 2019 Mar 18.