Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT1KNPI1)

• DOT Name: Creatine kinase S-type, mitochondrial (CKMT2)
• Synonyms: EC 2.7.3.2; Basic-type mitochondrial creatine kinase; Mib-CK; Sarcomeric mitochondrial creatine kinase; S-MtCK
• Gene Name: CKMT2
• Related Disease:
  Coronary atherosclerosis
  Coronary heart disease
  Myocardial infarction
  Stroke
  Advanced cancer
  Werner syndrome
  Acute myelogenous leukaemia
• UniProt ID: KCRS_HUMAN
• PDB ID: 4Z9M
• EC Number: 2.7.3.2
• Pfam ID: PF00217 ; PF02807
• Sequence:
  MASIFSKLLTGRNASLLFATMGTSVLTTGYLLNRQKVCAEVREQPRLFPPSADYPDLRKH
  NNCMAECLTPAIYAKLRNKVTPNGYTLDQCIQTGVDNPGHPFIKTVGMVAGDEESYEVFA
  DLFDPVIKLRHNGYDPRVMKHTTDLDASKITQGQFDEHYVLSSRVRTGRSIRGLSLPPAC
  TRAERREVENVAITALEGLKGDLAGRYYKLSEMTEQDQQRLIDDHFLFDKPVSPLLTCAG
  MARDWPDARGIWHNYDKTFLIWINEEDHTRVISMEKGGNMKRVFERFCRGLKEVERLIQE
  RGWEFMWNERLGYILTCPSNLGTGLRAGVHVRIPKLSKDPRFSKILENLRLQKRGTGGVD
  TAAVADVYDISNIDRIGRSEVELVQIVIDGVNYLVDCEKKLERGQDIKVPPPLPQFGKK
• 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.
• Tissue Specificity: Sarcomere-specific. Found only in heart and skeletal muscles.
• KEGG Pathway:
  Arginine and proline metabolism (hsa00330)
  Metabolic pathways (hsa01100)
• Reactome Pathway: Creatine metabolism (R-HSA-71288)
• BioCyc Pathway: MetaCyc:HS05555-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

7 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Coronary atherosclerosis	DISKNDYU	Definitive	Biomarker	[1]
Coronary heart disease	DIS5OIP1	Definitive	Biomarker	[1]
Myocardial infarction	DIS655KI	Definitive	Genetic Variation	[1]
Stroke	DISX6UHX	Definitive	Genetic Variation	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Werner syndrome	DISZY45W	moderate	Biomarker	[3]
Acute myelogenous leukaemia	DISCSPTN	Limited	Biomarker	[4]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Creatine kinase S-type, mitochondrial (CKMT2).	[5]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Creatine kinase S-type, mitochondrial (CKMT2).	[6]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Creatine kinase S-type, mitochondrial (CKMT2).	[7]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Creatine kinase S-type, mitochondrial (CKMT2).	[8]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Creatine kinase S-type, mitochondrial (CKMT2).	[9]
Nicotine	DMWX5CO	Approved	Nicotine decreases the expression of Creatine kinase S-type, mitochondrial (CKMT2).	[11]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Creatine kinase S-type, mitochondrial (CKMT2).	[12]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Creatine kinase S-type, mitochondrial (CKMT2).	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of Creatine kinase S-type, mitochondrial (CKMT2).	[10]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Creatine kinase S-type, mitochondrial (CKMT2).	[10]

References

• [1] Admixture Mapping of Subclinical Atherosclerosis and Subsequent Clinical Events Among African Americans in 2 Large Cohort Studies.Circ Cardiovasc Genet. 2017 Apr;10(2):e001569. doi: 10.1161/CIRCGENETICS.116.001569.
• [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] Common and cell type-specific responses of human cells to mitochondrial dysfunction.Exp Cell Res. 2005 Jan 15;302(2):270-80. doi: 10.1016/j.yexcr.2004.09.006.
• [4] Protein kinase CK2alpha as an unfavorable prognostic marker and novel therapeutic target in acute myeloid leukemia.Clin Cancer Res. 2007 Feb 1;13(3):1019-28. doi: 10.1158/1078-0432.CCR-06-1602.
• [5] Antiepileptic drugs are endocrine disruptors for the human fetal testis ex vivo. Toxicol Sci. 2023 Sep 28;195(2):169-183. doi: 10.1093/toxsci/kfad076.
• [6] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [7] Increased mitochondrial ROS formation by acetaminophen in human hepatic cells is associated with gene expression changes suggesting disruption of the mitochondrial electron transport chain. Toxicol Lett. 2015 Apr 16;234(2):139-50.
• [8] 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.
• [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] 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.
• [11] Nicotinic modulation of gene expression in SH-SY5Y neuroblastoma cells. Brain Res. 2006 Oct 20;1116(1):39-49.
• [12] Benzo[a]pyrene-induced changes in microRNA-mRNA networks. Chem Res Toxicol. 2012 Apr 16;25(4):838-49.
• [13] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.