Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT84OHHP)

• DOT Name: Adenylate kinase isoenzyme 6 (AK6)
• Synonyms: AK6; EC 2.7.4.3; Adrenal gland protein AD-004; Coilin-interacting nuclear ATPase protein; hCINAP; Dual activity adenylate kinase/ATPase; AK/ATPase
• Gene Name: AK6
• Related Disease:
  Acute myelogenous leukaemia
  Cardiac failure
  Cardiomyopathy
  Colorectal carcinoma
  Congestive heart failure
  Cryptococcosis
  Dyskeratosis congenita
  Early-onset anterior polar cataract
  Epithelial neoplasm
  Essential thrombocythemia
  Laryngeal carcinoma
  Lyme disease
  Neoplasm
  Ovarian cancer
  Prostate cancer
  Prostate carcinoma
  Advanced cancer
  Methicillin-resistant staphylococci infection
  Acute leukaemia
  Breast cancer
  Breast carcinoma
  Gastroparesis
  Leukemia
  Neuroendocrine neoplasm
• UniProt ID: KAD6_HUMAN
• PDB ID: 1RKB; 3IIJ; 3IIK; 3IIL; 3IIM; 5JZV
• EC Number: 2.7.4.3
• Pfam ID: PF13238
• Sequence:
  MLLPNILLTGTPGVGKTTLGKELASKSGLKYINVGDLAREEQLYDGYDEEYDCPILDEDR
  VVDELDNQMREGGVIVDYHGCDFFPERWFHIVFVLRTDTNVLYERLETRGYNEKKLTDNI
  QCEIFQVLYEEATASYKEEIVHQLPSNKPEELENNVDQILKWIEQWIKDHNS
• Function: Broad-specificity nucleoside monophosphate (NMP) kinase that catalyzes the reversible transfer of the terminal phosphate group between nucleoside triphosphates and monophosphates. Has also ATPase activity. Involved in the late cytoplasmic maturation steps of the 40S ribosomal particles, specifically 18S rRNA maturation. While NMP activity is not required for ribosome maturation, ATPase activity is. Associates transiently with small ribosomal subunit protein uS11. ATP hydrolysis breaks the interaction with uS11. May temporarily remove uS11 from the ribosome to enable a conformational change of the ribosomal RNA that is needed for the final maturation step of the small ribosomal subunit. Its NMP activity may have a role in nuclear energy homeostasis. AMP and dAMP are the preferred substrates, but CMP and dCMP are also good substrates. IMP is phosphorylated to a much lesser extent. All nucleoside triphosphates ATP, GTP, UTP, CTP, dATP, dCTP, dGTP, and TTP are accepted as phosphate donors. CTP is the best phosphate donor, followed by UTP, ATP, GTP and dCTP. May be involved in regulation of Cajal body (CB) formation.
• Tissue Specificity: Expressed in heart, brain, placenta, lung, liver, skeletal muscle, kidney, pancreas, chorionic villi and the central nervous system.
• KEGG Pathway:
  Purine metabolism (hsa00230)
  Metabolic pathways (hsa01100)
  Nucleotide metabolism (hsa01232)
  Biosynthesis of cofactors (hsa01240)
  Ribosome biogenesis in eukaryotes (hsa03008)
• Reactome Pathway: Interconversion of nucleotide di- and triphosphates (R-HSA-499943)

Molecular Interaction Atlas (MIA) of This DOT

24 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute myelogenous leukaemia	DISCSPTN	Strong	Biomarker	[1]
Cardiac failure	DISDC067	Strong	Genetic Variation	[2]
Cardiomyopathy	DISUPZRG	Strong	Genetic Variation	[2]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[3]
Congestive heart failure	DIS32MEA	Strong	Genetic Variation	[2]
Cryptococcosis	DISDYDTK	Strong	Biomarker	[4]
Dyskeratosis congenita	DISSXV0K	Strong	Biomarker	[5]
Early-onset anterior polar cataract	DISTOPIY	Strong	Biomarker	[6]
Epithelial neoplasm	DIS0T594	Strong	Altered Expression	[7]
Essential thrombocythemia	DISWWK11	Strong	Biomarker	[8]
Laryngeal carcinoma	DISNHCIV	Strong	Altered Expression	[9]
Lyme disease	DISO70G5	Strong	Biomarker	[10]
Neoplasm	DISZKGEW	Strong	Biomarker	[11]
Ovarian cancer	DISZJHAP	Strong	Biomarker	[12]
Prostate cancer	DISF190Y	Strong	Biomarker	[13]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[14]
Advanced cancer	DISAT1Z9	moderate	Biomarker	[11]
Methicillin-resistant staphylococci infection	DIS6DRDZ	moderate	Biomarker	[15]
Acute leukaemia	DISDQFDI	Limited	Altered Expression	[16]
Breast cancer	DIS7DPX1	Limited	Biomarker	[17]
Breast carcinoma	DIS2UE88	Limited	Biomarker	[17]
Gastroparesis	DISDW0SR	Limited	Genetic Variation	[18]
Leukemia	DISNAKFL	Limited	Posttranslational Modification	[16]
Neuroendocrine neoplasm	DISNPLOO	Limited	Biomarker	[19]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Adenylate kinase isoenzyme 6 (AK6).	[20]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Adenylate kinase isoenzyme 6 (AK6).	[21]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane increases the expression of Adenylate kinase isoenzyme 6 (AK6).	[22]

References

• [1] hCINAP regulates the DNA-damage response and mediates the resistance of acute myelocytic leukemia cells to therapy.Nat Commun. 2019 Aug 23;10(1):3812. doi: 10.1038/s41467-019-11795-5.
• [2] Cardiomyocyte-enriched protein CIP protects against pathophysiological stresses and regulates cardiac homeostasis.J Clin Invest. 2015 Nov 2;125(11):4122-34. doi: 10.1172/JCI82423. Epub 2015 Oct 5.
• [3] Adenylate kinase hCINAP determines self-renewal of colorectal cancer stem cells by facilitating LDHA phosphorylation.Nat Commun. 2017 May 18;8:15308. doi: 10.1038/ncomms15308.
• [4] Mycobacterium doricum sp. nov.Int J Syst Evol Microbiol. 2001 Nov;51(Pt 6):2007-2012. doi: 10.1099/00207713-51-6-2007.
• [5] The p53/p21(WAF/CIP) pathway mediates oxidative stress and senescence in dyskeratosis congenita cells with telomerase insufficiency.Antioxid Redox Signal. 2011 Mar 15;14(6):985-97. doi: 10.1089/ars.2010.3444. Epub 2011 Jan 17.
• [6] The changing epidemiology of community-acquired pneumonia: nationwide register-based study in Sweden.J Intern Med. 2019 Dec;286(6):689-701. doi: 10.1111/joim.12956. Epub 2019 Aug 13.
• [7] E6AP mediates regulated proteasomal degradation of the nuclear receptor coactivator amplified in breast cancer 1 in immortalized cells.Cancer Res. 2006 Sep 1;66(17):8680-6. doi: 10.1158/0008-5472.CAN-06-0557.
• [8] Clonal hemopoiesis and risk of thrombosis in young female patients with essential thrombocythemia.Exp Hematol. 2001 Jun;29(6):670-6. doi: 10.1016/s0301-472x(01)00640-3.
• [9] Clinical relevance of expression of the CIP/KIP cell-cycle inhibitors p21 and p27 in laryngeal cancer.J Clin Oncol. 1999 Oct;17(10):3150-9. doi: 10.1200/JCO.1999.17.10.3150.
• [10] Genomic and phenotypic characterization of Borrelia afzelii BO23 and Borrelia garinii CIP 103362.PLoS One. 2018 Jun 26;13(6):e0199641. doi: 10.1371/journal.pone.0199641. eCollection 2018.
• [11] The ATPase hCINAP regulates 18S rRNA processing and is essential for embryogenesis and tumour growth.Nat Commun. 2016 Aug 1;7:12310. doi: 10.1038/ncomms12310.
• [12] -Estradiol-dependent activation of the JAK/STAT pathway requires p/CIP and CARM1.Biochim Biophys Acta. 2013 Jun;1833(6):1463-75. doi: 10.1016/j.bbamcr.2013.02.009. Epub 2013 Feb 20.
• [13] PI3K-Akt signaling is involved in the regulation of p21(WAF/CIP) expression and androgen-independent growth in prostate cancer cells.Int J Oncol. 2006 Jan;28(1):245-51.
• [14] Ciz1 promotes tumorigenicity of prostate carcinoma cells.Front Biosci (Landmark Ed). 2015 Jan 1;20(4):705-15. doi: 10.2741/4331.
• [15] Synergistic antibacterial effect of Bi(2)S(3) nanospheres combined with ineffective antibiotic gentamicin against methicillin-resistant Staphylococcus aureus.J Inorg Biochem. 2017 Mar;168:38-45. doi: 10.1016/j.jinorgbio.2016.12.005. Epub 2016 Dec 10.
• [16] Epigenetic inactivation of the CIP/KIP cell-cycle control pathway in acute leukemias.Am J Hematol. 2005 Dec;80(4):282-7. doi: 10.1002/ajh.20503.
• [17] The KIP/CIP family members p21^{Waf1/Cip1} and p57^{Kip2} as diagnostic markers for breast cancer.Cancer Biomark. 2017;18(4):413-423. doi: 10.3233/CBM-160308.
• [18] Diagnosis and treatment of chronic gastroparesis and chronic intestinal pseudo-obstruction.Gastroenterol Clin North Am. 2003 Jun;32(2):619-58. doi: 10.1016/s0889-8553(03)00028-1.
• [19] BRD4 inhibitor IBET upregulates p27kip/cip protein stability in neuroendocrine tumor cells.Cancer Biol Ther. 2017 Apr 3;18(4):229-236. doi: 10.1080/15384047.2017.1294291. Epub 2017 Mar 10.
• [20] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [21] 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.
• [22] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.