Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT78PC0C)

• DOT Name: Myosin regulatory light chain 2, ventricular/cardiac muscle isoform (MYL2)
• Synonyms: MLC-2; MLC-2v; Cardiac myosin light chain 2; Myosin light chain 2, slow skeletal/ventricular muscle isoform; MLC-2s/v; Ventricular myosin light chain 2
• Gene Name: MYL2
• Related Disease:
  Hypertrophic cardiomyopathy
  Hypertrophic cardiomyopathy 10
  Restrictive cardiomyopathy
  Advanced cancer
  Bone osteosarcoma
  Brain neoplasm
  Cardiac failure
  Clear cell renal carcinoma
  Colon cancer
  Colon carcinoma
  Congenital diaphragmatic hernia
  Congestive heart failure
  Familial dilated cardiomyopathy
  Glioma
  Head and neck cancer
  Head and neck carcinoma
  Malignant soft tissue neoplasm
  Megalencephalic leukoencephalopathy with subcortical cysts
  Myopathy
  Neoplasm
  Obesity
  Osteosarcoma
  Renal cell carcinoma
  Sarcoma
  Type-1/2 diabetes
  Cardiomyopathy, familial restrictive, 1
  Familial hypertrophic cardiomyopathy
  High blood pressure
  Myopathy, myofibrillar, 12, infantile-onset, with cardiomyopathy
  Congenital fiber-type disproportion myopathy
  Cardiomyopathy
  Dilated cardiomyopathy
  Non-insulin dependent diabetes
  Arrhythmogenic right ventricular cardiomyopathy
• UniProt ID: MLRV_HUMAN
• PDB ID: 5TBY; 8ACT; 8G4L
• Pfam ID: PF13499
• Sequence:
  MAPKKAKKRAGGANSNVFSMFEQTQIQEFKEAFTIMDQNRDGFIDKNDLRDTFAALGRVN
  VKNEEIDEMIKEAPGPINFTVFLTMFGEKLKGADPEETILNAFKVFDPEGKGVLKADYVR
  EMLTTQAERFSKEEVDQMFAAFPPDVTGNLDYKNLVHIITHGEEKD
• Function: Contractile protein that plays a role in heart development and function. Following phosphorylation, plays a role in cross-bridge cycling kinetics and cardiac muscle contraction by increasing myosin lever arm stiffness and promoting myosin head diffusion; as a consequence of the increase in maximum contraction force and calcium sensitivity of contraction force. These events altogether slow down myosin kinetics and prolong duty cycle resulting in accumulated myosins being cooperatively recruited to actin binding sites to sustain thin filament activation as a means to fine-tune myofilament calcium sensitivity to force. During cardiogenesis plays an early role in cardiac contractility by promoting cardiac myofibril assembly.
• Tissue Specificity: Highly expressed in type I muscle fibers.
• KEGG Pathway:
  Cardiac muscle contraction (hsa04260)
  Adrenergic sig.ling in cardiomyocytes (hsa04261)
  Apelin sig.ling pathway (hsa04371)
  Focal adhesion (hsa04510)
  Adherens junction (hsa04520)
  Tight junction (hsa04530)
  Leukocyte transendothelial migration (hsa04670)
  Regulation of actin cytoskeleton (hsa04810)
  Motor proteins (hsa04814)
  Cytoskeleton in muscle cells (hsa04820)
  Shigellosis (hsa05131)
  Salmonella infection (hsa05132)
  Hypertrophic cardiomyopathy (hsa05410)
  Dilated cardiomyopathy (hsa05414)
• Reactome Pathway: Striated Muscle Contraction (R-HSA-390522)

Molecular Interaction Atlas (MIA) of This DOT

34 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hypertrophic cardiomyopathy	DISQG2AI	Definitive	Autosomal dominant	[1]
Hypertrophic cardiomyopathy 10	DISQOXW3	Definitive	Autosomal dominant	[1]
Restrictive cardiomyopathy	DISFAF31	Definitive	Genetic Variation	[2]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[3]
Bone osteosarcoma	DIST1004	Strong	Altered Expression	[4]
Brain neoplasm	DISY3EKS	Strong	Genetic Variation	[5]
Cardiac failure	DISDC067	Strong	Biomarker	[6]
Clear cell renal carcinoma	DISBXRFJ	Strong	Biomarker	[7]
Colon cancer	DISVC52G	Strong	Biomarker	[8]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[8]
Congenital diaphragmatic hernia	DIS0IPVU	Strong	Biomarker	[9]
Congestive heart failure	DIS32MEA	Strong	Biomarker	[6]
Familial dilated cardiomyopathy	DISBHDU9	Strong	Genetic Variation	[10]
Glioma	DIS5RPEH	Strong	Altered Expression	[11]
Head and neck cancer	DISBPSQZ	Strong	Biomarker	[12]
Head and neck carcinoma	DISOU1DS	Strong	Biomarker	[12]
Malignant soft tissue neoplasm	DISTC6NO	Strong	Altered Expression	[4]
Megalencephalic leukoencephalopathy with subcortical cysts	DISK9A1M	Strong	Genetic Variation	[13]
Myopathy	DISOWG27	Strong	Genetic Variation	[14]
Neoplasm	DISZKGEW	Strong	Biomarker	[7]
Obesity	DIS47Y1K	Strong	Genetic Variation	[15]
Osteosarcoma	DISLQ7E2	Strong	Altered Expression	[4]
Renal cell carcinoma	DISQZ2X8	Strong	Biomarker	[7]
Sarcoma	DISZDG3U	Strong	Altered Expression	[4]
Type-1/2 diabetes	DISIUHAP	Strong	Genetic Variation	[16]
Cardiomyopathy, familial restrictive, 1	DIS4AJ17	moderate	Biomarker	[17]
Familial hypertrophic cardiomyopathy	DISQ89HN	moderate	Genetic Variation	[18]
High blood pressure	DISY2OHH	moderate	Genetic Variation	[19]
Myopathy, myofibrillar, 12, infantile-onset, with cardiomyopathy	DISPBL05	Moderate	Autosomal recessive	[20]
Congenital fiber-type disproportion myopathy	DISU9T2M	Supportive	Autosomal dominant	[21]
Cardiomyopathy	DISUPZRG	Limited	Genetic Variation	[22]
Dilated cardiomyopathy	DISX608J	Limited	Autosomal dominant	[1]
Non-insulin dependent diabetes	DISK1O5Z	Limited	Genetic Variation	[23]
Arrhythmogenic right ventricular cardiomyopathy	DIS3V2BE	No Known	Autosomal dominant	[1]

8 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 Myosin regulatory light chain 2, ventricular/cardiac muscle isoform (MYL2).	[24]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Myosin regulatory light chain 2, ventricular/cardiac muscle isoform (MYL2).	[25]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Myosin regulatory light chain 2, ventricular/cardiac muscle isoform (MYL2).	[26]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Myosin regulatory light chain 2, ventricular/cardiac muscle isoform (MYL2).	[26]
Ethanol	DMDRQZU	Approved	Ethanol decreases the expression of Myosin regulatory light chain 2, ventricular/cardiac muscle isoform (MYL2).	[27]
Etoposide	DMNH3PG	Approved	Etoposide decreases the expression of Myosin regulatory light chain 2, ventricular/cardiac muscle isoform (MYL2).	[28]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Myosin regulatory light chain 2, ventricular/cardiac muscle isoform (MYL2).	[30]
QUERCITRIN	DM1DH96	Investigative	QUERCITRIN affects the expression of Myosin regulatory light chain 2, ventricular/cardiac muscle isoform (MYL2).	[31]

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 increases the methylation of Myosin regulatory light chain 2, ventricular/cardiac muscle isoform (MYL2).	[29]

References

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• [2] Allele-Specific Silencing Ameliorates Restrictive Cardiomyopathy Attributable to a Human Myosin Regulatory Light Chain Mutation.Circulation. 2019 Aug 27;140(9):765-778. doi: 10.1161/CIRCULATIONAHA.118.036965. Epub 2019 Jul 18.
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• [9] Embryonic essential myosin light chain regulates fetal lung development in rats.Am J Respir Cell Mol Biol. 2007 Sep;37(3):330-8. doi: 10.1165/rcmb.2006-0349OC. Epub 2007 May 31.
• [10] Novel familial dilated cardiomyopathy mutation in MYL2 affects the structure and function of myosin regulatory light chain.FEBS J. 2015 Jun;282(12):2379-93. doi: 10.1111/febs.13286. Epub 2015 Apr 16.
• [11] Mer receptor tyrosine kinase promotes invasion and survival in glioblastoma multiforme.Oncogene. 2013 Feb 14;32(7):872-82. doi: 10.1038/onc.2012.104. Epub 2012 Apr 2.
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• [13] Leukoencephalopathy associated with 11q24 deletion involving the gene encoding hepatic and glial cell adhesion molecule in two patients.Eur J Med Genet. 2015 Sep;58(9):492-6. doi: 10.1016/j.ejmg.2015.06.008. Epub 2015 Jul 17.
• [14] Slow-twitch skeletal muscle defects accompany cardiac dysfunction in transgenic mice with a mutation in the myosin regulatory light chain.FASEB J. 2019 Mar;33(3):3152-3166. doi: 10.1096/fj.201801402R. Epub 2018 Oct 26.
• [15] Effect of obesity on the association between MYL2 (rs3782889) and high-density lipoprotein cholesterol among Korean men.J Hum Genet. 2016 May;61(5):405-9. doi: 10.1038/jhg.2015.165. Epub 2016 Jan 14.
• [16] Genome-wide association study of clinically defined gout identifies multiple risk loci and its association with clinical subtypes.Ann Rheum Dis. 2016 Apr;75(4):652-9. doi: 10.1136/annrheumdis-2014-206191. Epub 2015 Feb 2.
• [17] Furthering the link between the sarcomere and primary cardiomyopathies: restrictive cardiomyopathy associated with multiple mutations in genes previously associated with hypertrophic or dilated cardiomyopathy.Am J Med Genet A. 2011 Sep;155A(9):2229-35. doi: 10.1002/ajmg.a.34097. Epub 2011 Aug 5.
• [18] Therapeutic potential of AAV9-S15D-RLC gene delivery in humanized MYL2 mouse model of HCM.J Mol Med (Berl). 2019 Jul;97(7):1033-1047. doi: 10.1007/s00109-019-01791-z. Epub 2019 May 17.
• [19] Hypertrophic remodelling in cardiac regulatory myosin light chain (MYL2) founder mutation carriers.Eur Heart J. 2016 Jun 14;37(23):1815-22. doi: 10.1093/eurheartj/ehv522. Epub 2015 Oct 24.
• [20] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [21] Recessive MYL2 mutations cause infantile type I muscle fibre disease and cardiomyopathy. Brain. 2013 Jan;136(Pt 1):282-93. doi: 10.1093/brain/aws293.
• [22] The co-segregation of the MYL2 R58Q mutation in Chinese hypertrophic cardiomyopathy family and its pathological effect on cardiomyopathy disarray.Mol Genet Genomics. 2019 Oct;294(5):1241-1249. doi: 10.1007/s00438-019-01578-4. Epub 2019 May 18.
• [23] New susceptibility loci in MYL2, C12orf51 and OAS1 associated with 1-h plasma glucose as predisposing risk factors for type 2 diabetes in the Korean population.J Hum Genet. 2013 Jun;58(6):362-5. doi: 10.1038/jhg.2013.14. Epub 2013 Apr 11.
• [24] Atrial-like Engineered Heart Tissue: An In?Vitro Model of the Human Atrium. Stem Cell Reports. 2018 Dec 11;11(6):1378-1390. doi: 10.1016/j.stemcr.2018.10.008. Epub 2018 Nov 8.
• [25] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [26] Functional cardiotoxicity assessment of cosmetic compounds using human-induced pluripotent stem cell-derived cardiomyocytes. Arch Toxicol. 2018 Jan;92(1):371-381.
• [27] Cardiac toxicity from ethanol exposure in human-induced pluripotent stem cell-derived cardiomyocytes. Toxicol Sci. 2019 May 1;169(1):280-292.
• [28] Cell death mechanisms of the anti-cancer drug etoposide on human cardiomyocytes isolated from pluripotent stem cells. Arch Toxicol. 2018 Apr;92(4):1507-1524.
• [29] 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.
• [30] 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.
• [31] Molecular mechanisms of quercitrin-induced apoptosis in non-small cell lung cancer. Arch Med Res. 2014 Aug;45(6):445-54.