Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTCINHH5)

• DOT Name: Creatine kinase U-type, mitochondrial (CKMT1A)
• Synonyms: EC 2.7.3.2; Acidic-type mitochondrial creatine kinase; Mia-CK; Ubiquitous mitochondrial creatine kinase; U-MtCK
• Gene Name: CKMT1A
• Related Disease:
  Acute myelogenous leukaemia
  Colon adenocarcinoma
  Colorectal carcinoma
  Head and neck carcinoma
  Head-neck squamous cell carcinoma
  Neoplasm
  Squamous cell carcinoma
  Advanced cancer
  Hepatocellular carcinoma
  Nasopharyngeal carcinoma
• UniProt ID: KCRU_HUMAN
• PDB ID: 1QK1
• EC Number: 2.7.3.2
• Pfam ID: PF00217 ; PF02807
• Sequence:
  MAGPFSRLLSARPGLRLLALAGAGSLAAGFLLRPEPVRAASERRRLYPPSAEYPDLRKHN
  NCMASHLTPAVYARLCDKTTPTGWTLDQCIQTGVDNPGHPFIKTVGMVAGDEETYEVFAD
  LFDPVIQERHNGYDPRTMKHTTDLDASKIRSGYFDERYVLSSRVRTGRSIRGLSLPPACT
  RAERREVERVVVDALSGLKGDLAGRYYRLSEMTEAEQQQLIDDHFLFDKPVSPLLTAAGM
  ARDWPDARGIWHNNEKSFLIWVNEEDHTRVISMEKGGNMKRVFERFCRGLKEVERLIQER
  GWEFMWNERLGYILTCPSNLGTGLRAGVHIKLPLLSKDSRFPKILENLRLQKRGTGGVDT
  AATGGVFDISNLDRLGKSEVELVQLVIDGVNYLIDCERRLERGQDIRIPTPVIHTKH
• Function: Reversibly catalyzes the transfer of phosphate between ATP and various phosphogens (e.g. creatine phosphate). Creatine kinase isoenzymes play a central role in energy transduction in tissues with large, fluctuating energy demands, such as skeletal muscle, heart, brain and spermatozoa.
• KEGG Pathway:
  Arginine and proline metabolism (hsa00330)
  Metabolic pathways (hsa01100)
• Reactome Pathway: Creatine metabolism (R-HSA-71288)
• BioCyc Pathway: MetaCyc:HS09820-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
Acute myelogenous leukaemia	DISCSPTN	Strong	Biomarker	[1]
Colon adenocarcinoma	DISDRE0J	Strong	Altered Expression	[2]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[3]
Head and neck carcinoma	DISOU1DS	Strong	Altered Expression	[4]
Head-neck squamous cell carcinoma	DISF7P24	Strong	Altered Expression	[4]
Neoplasm	DISZKGEW	Strong	Altered Expression	[5]
Squamous cell carcinoma	DISQVIFL	Strong	Altered Expression	[5]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[6]
Hepatocellular carcinoma	DIS0J828	Limited	Biomarker	[7]
Nasopharyngeal carcinoma	DISAOTQ0	Limited	Biomarker	[6]

This DOT Affected the Drug Response of 5 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Cisplatin	DMRHGI9	Approved	Creatine kinase U-type, mitochondrial (CKMT1A) affects the response to substance of Cisplatin.	[15]
Methotrexate	DM2TEOL	Approved	Creatine kinase U-type, mitochondrial (CKMT1A) affects the response to substance of Methotrexate.	[15]
Etoposide	DMNH3PG	Approved	Creatine kinase U-type, mitochondrial (CKMT1A) affects the response to substance of Etoposide.	[15]
Mitomycin	DMH0ZJE	Approved	Creatine kinase U-type, mitochondrial (CKMT1A) affects the response to substance of Mitomycin.	[15]
Afimoxifene	DMFORDT	Phase 2	Creatine kinase U-type, mitochondrial (CKMT1A) decreases the response to substance of Afimoxifene.	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Creatine kinase U-type, mitochondrial (CKMT1A).	[8]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Creatine kinase U-type, mitochondrial (CKMT1A).	[9]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Creatine kinase U-type, mitochondrial (CKMT1A).	[10]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of Creatine kinase U-type, mitochondrial (CKMT1A).	[11]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the expression of Creatine kinase U-type, mitochondrial (CKMT1A).	[13]
Dibutyl phthalate	DMEDGKO	Investigative	Dibutyl phthalate increases the expression of Creatine kinase U-type, mitochondrial (CKMT1A).	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Creatine kinase U-type, mitochondrial (CKMT1A).	[12]

References

• [1] The creatine kinase pathway is a metabolic vulnerability in EVI1-positive acute myeloid leukemia.Nat Med. 2017 Mar;23(3):301-313. doi: 10.1038/nm.4283. Epub 2017 Feb 13.
• [2] Progressive decrease of phosphocreatine, creatine and creatine kinase in skeletal muscle upon transformation to sarcoma.FEBS J. 2008 Jun;275(12):3236-47. doi: 10.1111/j.1742-4658.2008.06475.x. Epub 2008 May 13.
• [3] MiR-519b-3p Inhibits the Proliferation and Invasion in Colorectal Cancer via Modulating the uMtCK/Wnt Signaling Pathway.Front Pharmacol. 2019 Jul 2;10:741. doi: 10.3389/fphar.2019.00741. eCollection 2019.
• [4] CKMT1 and NCOA1 expression as a predictor of clinical outcome in patients with advanced-stage head and neck squamous cell carcinoma.Head Neck. 2016 Apr;38 Suppl 1:E1392-403. doi: 10.1002/hed.24232. Epub 2015 Oct 30.
• [5] Ubiquitous mitochondrial creatine kinase downregulated in oral squamous cell carcinoma.Br J Cancer. 2006 Mar 13;94(5):698-709. doi: 10.1038/sj.bjc.6602986.
• [6] Effects of CKMT1 on radiosensitivity of nasopharyngeal carcinoma cells.Int J Radiat Biol. 2019 May;95(5):597-606. doi: 10.1080/09553002.2019.1554919. Epub 2019 Jan 4.
• [7] LncRNA n335586/miR-924/CKMT1A axis contributes to cell migration and invasion in hepatocellular carcinoma cells.Cancer Lett. 2018 Aug 10;429:89-99. doi: 10.1016/j.canlet.2018.05.010. Epub 2018 May 16.
• [8] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [9] 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.
• [10] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [11] Folic acid supplementation dysregulates gene expression in lymphoblastoid cells--implications in nutrition. Biochem Biophys Res Commun. 2011 Sep 9;412(4):688-92. doi: 10.1016/j.bbrc.2011.08.027. Epub 2011 Aug 16.
• [12] 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.
• [13] Transcriptome profile analysis of saturated aliphatic aldehydes reveals carbon number-specific molecules involved in pulmonary toxicity. Chem Res Toxicol. 2014 Aug 18;27(8):1362-70.
• [14] In Vitro Exposure of Human Luteinized Mural Granulosa Cells to Dibutyl Phthalate Affects Global Gene Expression. Toxicol Sci. 2017 Nov 1;160(1):180-188. doi: 10.1093/toxsci/kfx170.
• [15] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.
• [16] High-throughput ectopic expression screen for tamoxifen resistance identifies an atypical kinase that blocks autophagy. Proc Natl Acad Sci U S A. 2011 Feb 1;108(5):2058-63.