Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTLI0HRU)

• DOT Name: Guanylate kinase (GUK1)
• Synonyms: EC 2.7.4.8; GMP kinase; Guanylate kinase 1
• Gene Name: GUK1
• Related Disease:
  Adenoma
  Advanced cancer
  Autism
  B-cell neoplasm
  Lung adenocarcinoma
  Schizophrenia
  Steroid-resistant nephrotic syndrome
  Intellectual disability
  Neoplasm
  Neurodevelopmental disorder
• UniProt ID: KGUA_HUMAN
• PDB ID: 6NUI
• EC Number: 2.7.4.8
• Pfam ID: PF00625
• Sequence:
  MSGPRPVVLSGPSGAGKSTLLKRLLQEHSGIFGFSVSHTTRNPRPGEENGKDYYFVTREV
  MQRDIAAGDFIEHAEFSGNLYGTSKVAVQAVQAMNRICVLDVDLQGVRNIKATDLRPIYI
  SVQPPSLHVLEQRLRQRNTETEESLVKRLAAAQADMESSKEPGLFDVVIINDSLDQAYAE
  LKEALSEEIKKAQRTGA
• Function: Catalyzes the phosphorylation of GMP to GDP. Essential enzyme for recycling GMP and indirectly, cyclic GMP (cGMP). Involved in the cGMP metabolism in photoreceptors. It may also have a role in the survival and growth progression of some tumors. In addition to its physiological role, GUK1 is essential for convert prodrugs used for the treatment of cancers and viral infections into their pharmacologically active metabolites, most notably acyclovir, ganciclovir, and 6-thioguanine and its closely related analog 6-mercaptopurine.
• Tissue Specificity: Widely expressed.
• KEGG Pathway:
  Purine metabolism (hsa00230)
  Metabolic pathways (hsa01100)
  Nucleotide metabolism (hsa01232)
• Reactome Pathway:
  Azathioprine ADME (R-HSA-9748787)
  Interconversion of nucleotide di- and triphosphates (R-HSA-499943)
• BioCyc Pathway: MetaCyc:HS07104-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

10 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adenoma	DIS78ZEV	Strong	Altered Expression	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Autism	DISV4V1Z	Strong	Genetic Variation	[3]
B-cell neoplasm	DISVY326	Strong	Biomarker	[4]
Lung adenocarcinoma	DISD51WR	Strong	Biomarker	[2]
Schizophrenia	DISSRV2N	Strong	Genetic Variation	[3]
Steroid-resistant nephrotic syndrome	DISVEBC9	Strong	Biomarker	[5]
Intellectual disability	DISMBNXP	Disputed	Genetic Variation	[6]
Neoplasm	DISZKGEW	Limited	Biomarker	[7]
Neurodevelopmental disorder	DIS372XH	Limited	Biomarker	[8]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Guanylate kinase (GUK1).	[9]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Guanylate kinase (GUK1).	[10]
Aspirin	DM672AH	Approved	Aspirin decreases the expression of Guanylate kinase (GUK1).	[12]
Azacitidine	DMTA5OE	Approved	Azacitidine increases the expression of Guanylate kinase (GUK1).	[13]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Guanylate kinase (GUK1).	[14]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Guanylate kinase (GUK1).	[15]
chloropicrin	DMSGBQA	Investigative	chloropicrin decreases the expression of Guanylate kinase (GUK1).	[17]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Guanylate kinase (GUK1).	[11]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Guanylate kinase (GUK1).	[16]

References

• [1] Hepatocyte growth factor-regulated tyrosine kinase substrate (HGS) and guanylate kinase 1 (GUK1) are differentially expressed in GH-secreting adenomas.Pituitary. 2006;9(2):83-92. doi: 10.1007/s11102-006-9277-1.
• [2] Solution structure and functional investigation of human guanylate kinase reveals allosteric networking and a crucial role for the enzyme in cancer.J Biol Chem. 2019 Aug 2;294(31):11920-11933. doi: 10.1074/jbc.RA119.009251. Epub 2019 Jun 14.
• [3] A Rare Variant Identified Within the GluN2B C-Terminus in a Patient with Autism Affects NMDA Receptor Surface Expression and Spine Density.J Neurosci. 2017 Apr 12;37(15):4093-4102. doi: 10.1523/JNEUROSCI.0827-16.2017. Epub 2017 Mar 10.
• [4] Assembly mechanism of the CARMA1-BCL10-MALT1-TRAF6 signalosome.Proc Natl Acad Sci U S A. 2018 Feb 13;115(7):1499-1504. doi: 10.1073/pnas.1721967115. Epub 2018 Jan 30.
• [5] MAGI2 Mutations Cause Congenital Nephrotic Syndrome.J Am Soc Nephrol. 2017 May;28(5):1614-1621. doi: 10.1681/ASN.2016040387. Epub 2016 Dec 8.
• [6] Synaptic Targeting and Function of SAPAPs Mediated by Phosphorylation-Dependent Binding to PSD-95 MAGUKs.Cell Rep. 2017 Dec 26;21(13):3781-3793. doi: 10.1016/j.celrep.2017.11.107.
• [7] Characterization of a novel human cell-cycle-regulated homologue of Drosophila dlg1.Genomics. 2001 Sep;77(1-2):5-7. doi: 10.1006/geno.2001.6570.
• [8] Deficiency of calcium/calmodulin-dependent serine protein kinase disrupts the excitatory-inhibitory balance of synapses by down-regulating GluN2B.Mol Psychiatry. 2019 Jul;24(7):1079-1092. doi: 10.1038/s41380-018-0338-4. Epub 2019 Jan 4.
• [9] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [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] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [12] Expression profile analysis of human peripheral blood mononuclear cells in response to aspirin. Arch Immunol Ther Exp (Warsz). 2005 Mar-Apr;53(2):151-8.
• [13] The effect of DNA methylation inhibitor 5-Aza-2'-deoxycytidine on human endometrial stromal cells. Hum Reprod. 2010 Nov;25(11):2859-69.
• [14] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [15] 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.
• [16] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [17] Molecular targets of chloropicrin in human airway epithelial cells. Toxicol In Vitro. 2017 Aug;42:247-254.