Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTJ6FM9F)

• DOT Name: Glucose-6-phosphatase catalytic subunit 1 (G6PC1)
• Synonyms: EC 3.1.3.9; Glucose-6-phosphatase; G-6-Pase; G6Pase; Glucose-6-phosphatase alpha; G6Pase-alpha
• Gene Name: G6PC1
• Related Disease: Glycogen storage disease type IA
• UniProt ID: G6PC1_HUMAN
• EC Number: 3.1.3.9
• Pfam ID: PF01569
• Sequence:
  MEEGMNVLHDFGIQSTHYLQVNYQDSQDWFILVSVIADLRNAFYVLFPIWFHLQEAVGIK
  LLWVAVIGDWLNLVFKWILFGQRPYWWVLDTDYYSNTSVPLIKQFPVTCETGPGSPSGHA
  MGTAGVYYVMVTSTLSIFQGKIKPTYRFRCLNVILWLGFWAVQLNVCLSRIYLAAHFPHQ
  VVAGVLSGIAVAETFSHIHSIYNASLKKYFLITFFLFSFAIGFYLLLKGLGVDLLWTLEK
  AQRWCEQPEWVHIDTTPFASLLKNLGTLFGLGLALNSSMYRESCKGKLSKWLPFRLSSIV
  ASLVLLHVFDSLKPPSQVELVFYVLSFCKSAVVPLASVSVIPYCLAQVLGQPHKKSL
• Function: Hydrolyzes glucose-6-phosphate to glucose in the endoplasmic reticulum. Forms with the glucose-6-phosphate transporter (SLC37A4/G6PT) the complex responsible for glucose production in the terminal step of glycogenolysis and gluconeogenesis. Hence, it is the key enzyme in homeostatic regulation of blood glucose levels.
• KEGG Pathway:
  Glycolysis / Gluconeogenesis (hsa00010)
  Galactose metabolism (hsa00052)
  Starch and sucrose metabolism (hsa00500)
  Metabolic pathways (hsa01100)
  FoxO sig.ling pathway (hsa04068)
  PI3K-Akt sig.ling pathway (hsa04151)
  AMPK sig.ling pathway (hsa04152)
  Insulin sig.ling pathway (hsa04910)
  Adipocytokine sig.ling pathway (hsa04920)
  Glucagon sig.ling pathway (hsa04922)
  Insulin resistance (hsa04931)
  Carbohydrate digestion and absorption (hsa04973)
• Reactome Pathway:
  Gluconeogenesis (R-HSA-70263)
  FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes (R-HSA-9615017)
  Glycogen storage disease type Ia (G6PC) (R-HSA-3274531)
• BioCyc Pathway: MetaCyc:HS05538-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Glycogen storage disease type IA	DISZSMKQ	Definitive	Autosomal recessive	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Prochlorperazine	DM53SRA	Approved	Glucose-6-phosphatase catalytic subunit 1 (G6PC1) increases the Metabolic disorder ADR of Prochlorperazine.	[26]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Glucose-6-phosphatase catalytic subunit 1 (G6PC1).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Glucose-6-phosphatase catalytic subunit 1 (G6PC1).	[3]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Glucose-6-phosphatase catalytic subunit 1 (G6PC1).	[4]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Glucose-6-phosphatase catalytic subunit 1 (G6PC1).	[2]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Glucose-6-phosphatase catalytic subunit 1 (G6PC1).	[5]
Phenobarbital	DMXZOCG	Approved	Phenobarbital decreases the expression of Glucose-6-phosphatase catalytic subunit 1 (G6PC1).	[6]
Dexamethasone	DMMWZET	Approved	Dexamethasone decreases the expression of Glucose-6-phosphatase catalytic subunit 1 (G6PC1).	[7]
Troglitazone	DM3VFPD	Approved	Troglitazone decreases the expression of Glucose-6-phosphatase catalytic subunit 1 (G6PC1).	[8]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone decreases the expression of Glucose-6-phosphatase catalytic subunit 1 (G6PC1).	[8]
Fenofibrate	DMFKXDY	Approved	Fenofibrate decreases the expression of Glucose-6-phosphatase catalytic subunit 1 (G6PC1).	[8]
Rifampicin	DM5DSFZ	Approved	Rifampicin decreases the expression of Glucose-6-phosphatase catalytic subunit 1 (G6PC1).	[9]
Liothyronine	DM6IR3P	Approved	Liothyronine increases the expression of Glucose-6-phosphatase catalytic subunit 1 (G6PC1).	[10]
Fluoxetine	DM3PD2C	Approved	Fluoxetine decreases the expression of Glucose-6-phosphatase catalytic subunit 1 (G6PC1).	[11]
Bosentan	DMIOGBU	Approved	Bosentan affects the expression of Glucose-6-phosphatase catalytic subunit 1 (G6PC1).	[12]
Mitotane	DMU1GX0	Approved	Mitotane decreases the expression of Glucose-6-phosphatase catalytic subunit 1 (G6PC1).	[13]
Teriflunomide	DMQ2FKJ	Approved	Teriflunomide increases the expression of Glucose-6-phosphatase catalytic subunit 1 (G6PC1).	[14]
Clopidogrel	DMOL54H	Approved	Clopidogrel decreases the expression of Glucose-6-phosphatase catalytic subunit 1 (G6PC1).	[13]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Glucose-6-phosphatase catalytic subunit 1 (G6PC1).	[15]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Glucose-6-phosphatase catalytic subunit 1 (G6PC1).	[16]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Glucose-6-phosphatase catalytic subunit 1 (G6PC1).	[14]
Clemizole	DM4UAPD	Phase 1	Clemizole increases the expression of Glucose-6-phosphatase catalytic subunit 1 (G6PC1).	[13]
Wortmannin	DM8EVK5	Terminated	Wortmannin increases the expression of Glucose-6-phosphatase catalytic subunit 1 (G6PC1).	[18]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Glucose-6-phosphatase catalytic subunit 1 (G6PC1).	[19]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A decreases the expression of Glucose-6-phosphatase catalytic subunit 1 (G6PC1).	[20]
D-glucose	DMMG2TO	Investigative	D-glucose increases the expression of Glucose-6-phosphatase catalytic subunit 1 (G6PC1).	[21]
OXYQUINOLINE	DMZVS9Y	Investigative	OXYQUINOLINE increases the expression of Glucose-6-phosphatase catalytic subunit 1 (G6PC1).	[5]
2-AMINO-1-METHYL-6-PHENYLIMIDAZO[4,5-B]PYRIDINE	DMNQL17	Investigative	2-AMINO-1-METHYL-6-PHENYLIMIDAZO[4,5-B]PYRIDINE increases the expression of Glucose-6-phosphatase catalytic subunit 1 (G6PC1).	[22]
Chlorpyrifos	DMKPUI6	Investigative	Chlorpyrifos decreases the expression of Glucose-6-phosphatase catalytic subunit 1 (G6PC1).	[23]
NSC-1771	DMNXDGQ	Investigative	NSC-1771 decreases the expression of Glucose-6-phosphatase catalytic subunit 1 (G6PC1).	[23]
CITCO	DM0N634	Investigative	CITCO decreases the expression of Glucose-6-phosphatase catalytic subunit 1 (G6PC1).	[6]
BETULIN	DMGQRON	Investigative	BETULIN decreases the expression of Glucose-6-phosphatase catalytic subunit 1 (G6PC1).	[24]
Ginsenoside Re	DM46FVD	Investigative	Ginsenoside Re decreases the expression of Glucose-6-phosphatase catalytic subunit 1 (G6PC1).	[25]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
T83193	DMHO29Y	Patented	T83193 affects the binding of Glucose-6-phosphatase catalytic subunit 1 (G6PC1).	[17]

References

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• [11] Downregulation of glucose-6-phosphatase expression contributes to fluoxetine-induced hepatic steatosis. J Appl Toxicol. 2021 Aug;41(8):1232-1240. doi: 10.1002/jat.4109. Epub 2020 Nov 12.
• [12] Omics-based responses induced by bosentan in human hepatoma HepaRG cell cultures. Arch Toxicol. 2018 Jun;92(6):1939-1952.
• [13] Identification of novel agonists by high-throughput screening and molecular modelling of human constitutive androstane receptor isoform 3. Arch Toxicol. 2019 Aug;93(8):2247-2264. doi: 10.1007/s00204-019-02495-6. Epub 2019 Jul 16.
• [14] Teriflunomide is an indirect human constitutive androstane receptor (CAR) activator interacting with epidermal growth factor (EGF) signaling. Front Pharmacol. 2018 Oct 11;9:993.
• [15] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
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• [17] Vanillin exerts therapeutic effects against hyperglycemia-altered glucose metabolism and purinergic activities in testicular tissues of diabetic rats. Reprod Toxicol. 2021 Jun;102:24-34. doi: 10.1016/j.reprotox.2021.03.007. Epub 2021 Apr 3.
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• [22] Heterocyclic amines reduce insulin-induced AKT phosphorylation and induce gluconeogenic gene expression in human hepatocytes. Arch Toxicol. 2023 Jun;97(6):1613-1626. doi: 10.1007/s00204-023-03488-2. Epub 2023 Apr 2.
• [23] RNA-protein correlation of liver toxicity markers in HepaRG cells. EXCLI J. 2020 Jan 17;19:135-153. doi: 10.17179/excli2019-2005. eCollection 2020.
• [24] Anti-inflammatory action of betulin and its potential as a dissociated glucocorticoid receptor modulator. Food Chem Toxicol. 2021 Nov;157:112539. doi: 10.1016/j.fct.2021.112539. Epub 2021 Sep 7.
• [25] Ginsenoside Re lowers blood glucose and lipid levels via activation of AMP-activated protein kinase in HepG2 cells and high-fat diet fed mice. Int J Mol Med. 2012 Jan;29(1):73-80. doi: 10.3892/ijmm.2011.805. Epub 2011 Oct 3.
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