Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTKD3RSX)

• DOT Name: Myosin light chain 3 (MYL3)
• Synonyms: Cardiac myosin light chain 1; CMLC1; Myosin light chain 1, slow-twitch muscle B/ventricular isoform; MLC1SB; Ventricular myosin alkali light chain; Ventricular myosin light chain 1; VLCl; Ventricular/slow twitch myosin alkali light chain; MLC-lV/sb
• Gene Name: MYL3
• Related Disease:
  Hypertrophic cardiomyopathy
  Hypertrophic cardiomyopathy 8
  Acute myocardial infarction
  Breast carcinoma
  Cardiac disease
  Cardiac failure
  Cardiomyopathy
  Congenital heart disease
  Congestive heart failure
  Dilated cardiomyopathy 1A
  Familial hypertrophic cardiomyopathy
  Hereditary hemochromatosis
  High blood pressure
  Hypertrophic cardiomyopathy 1
  Cardiomyopathy, familial restrictive, 1
  Dilated cardiomyopathy
  Arrhythmogenic right ventricular cardiomyopathy
  Central core myopathy
  Cleidocranial dysplasia 1
• UniProt ID: MYL3_HUMAN
• PDB ID: 5TBY; 8ACT; 8G4L
• Sequence:
  MAPKKPEPKKDDAKAAPKAAPAPAPPPEPERPKEVEFDASKIKIEFTPEQIEEFKEAFML
  FDRTPKCEMKITYGQCGDVLRALGQNPTQAEVLRVLGKPRQEELNTKMMDFETFLPMLQH
  ISKNKDTGTYEDFVEGLRVFDKEGNGTVMGAELRHVLATLGERLTEDEVEKLMAGQEDSN
  GCINYEAFVKHIMSS
• Function: Regulatory light chain of myosin. Does not bind calcium.
• KEGG Pathway:
  Cardiac muscle contraction (hsa04260)
  Adrenergic sig.ling in cardiomyocytes (hsa04261)
  Apelin sig.ling pathway (hsa04371)
  Motor proteins (hsa04814)
  Cytoskeleton in muscle cells (hsa04820)
  Hypertrophic cardiomyopathy (hsa05410)
  Dilated cardiomyopathy (hsa05414)
• Reactome Pathway: Striated Muscle Contraction (R-HSA-390522)

Molecular Interaction Atlas (MIA) of This DOT

19 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 8	DIS0VJ91	Definitive	Autosomal dominant	[2]
Acute myocardial infarction	DISE3HTG	Strong	Biomarker	[3]
Breast carcinoma	DIS2UE88	Strong	Genetic Variation	[4]
Cardiac disease	DISVO1I5	Strong	Genetic Variation	[5]
Cardiac failure	DISDC067	Strong	Genetic Variation	[6]
Cardiomyopathy	DISUPZRG	Strong	Genetic Variation	[7]
Congenital heart disease	DISQBA23	Strong	Altered Expression	[8]
Congestive heart failure	DIS32MEA	Strong	Genetic Variation	[6]
Dilated cardiomyopathy 1A	DIS0RK9Z	Strong	Genetic Variation	[9]
Familial hypertrophic cardiomyopathy	DISQ89HN	Strong	CausalMutation	[10]
Hereditary hemochromatosis	DISVG5MT	Strong	Biomarker	[11]
High blood pressure	DISY2OHH	Strong	Biomarker	[12]
Hypertrophic cardiomyopathy 1	DISFOPCJ	Strong	Genetic Variation	[13]
Cardiomyopathy, familial restrictive, 1	DIS4AJ17	moderate	Genetic Variation	[14]
Dilated cardiomyopathy	DISX608J	Disputed	Autosomal dominant	[1]
Arrhythmogenic right ventricular cardiomyopathy	DIS3V2BE	Limited	Autosomal dominant	[1]
Central core myopathy	DIS18AZZ	Limited	Altered Expression	[15]
Cleidocranial dysplasia 1	DIS2OHLA	Limited	Altered Expression	[15]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Myosin light chain 3 (MYL3).	[16]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Myosin light chain 3 (MYL3).	[21]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Myosin light chain 3 (MYL3).	[23]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Myosin light chain 3 (MYL3).	[17]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Myosin light chain 3 (MYL3).	[18]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of Myosin light chain 3 (MYL3).	[19]
Etoposide	DMNH3PG	Approved	Etoposide decreases the expression of Myosin light chain 3 (MYL3).	[20]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Myosin light chain 3 (MYL3).	[22]

References

• [1] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [2] Results of clinical genetic testing of 2,912 probands with hypertrophic cardiomyopathy: expanded panels offer limited additional sensitivity. Genet Med. 2015 Nov;17(11):880-8. doi: 10.1038/gim.2014.205. Epub 2015 Jan 22.
• [3] mRNA expression patterns in human myocardial tissue, pericardial fluid and blood, and its contribution to the diagnosis of cause of death.Forensic Sci Int. 2019 Sep;302:109876. doi: 10.1016/j.forsciint.2019.109876. Epub 2019 Jul 25.
• [4] Association analysis identifies 65 new breast cancer risk loci.Nature. 2017 Nov 2;551(7678):92-94. doi: 10.1038/nature24284. Epub 2017 Oct 23.
• [5] Determining the Pathogenicity of a Genomic Variant of Uncertain Significance Using CRISPR/Cas9 and Human-Induced Pluripotent Stem Cells.Circulation. 2018 Dec 4;138(23):2666-2681. doi: 10.1161/CIRCULATIONAHA.117.032273.
• [6] Long-term outcome of 4 Korean families with hypertrophic cardiomyopathy caused by 4 different mutations.Clin Cardiol. 2010 Jul;33(7):430-8. doi: 10.1002/clc.20795.
• [7] A Complete Absence of Missense Mutation in Myosin Regulatory and Essential Light Chain Genes of South Indian Hypertrophic and Dilated Cardiomyopathies.Cardiology. 2018;141(3):156-166. doi: 10.1159/000495027. Epub 2019 Jan 3.
• [8] Human atrial myosin light chain 1 expression attenuates heart failure.Adv Exp Med Biol. 2005;565:283-92; discussion 92, 405-15. doi: 10.1007/0-387-24990-7_21.
• [9] Targeted next-generation sequencing of candidate genes reveals novel mutations in patients with dilated cardiomyopathy.Int J Mol Med. 2015 Dec;36(6):1479-86. doi: 10.3892/ijmm.2015.2361. Epub 2015 Oct 7.
• [10] Reassessment of Mendelian gene pathogenicity using 7,855 cardiomyopathy cases and 60,706 reference samples.Genet Med. 2017 Feb;19(2):192-203. doi: 10.1038/gim.2016.90. Epub 2016 Aug 17.
• [11] High-throughput single-strand conformation polymorphism analysis on a microfabricated capillary array electrophoresis device.Electrophoresis. 2005 May;26(9):1834-42. doi: 10.1002/elps.200410205.
• [12] Ventricular myosin light chain 1 is developmentally regulated and does not change in hypertension.Nucleic Acids Res. 1989 Apr 11;17(7):2753-67. doi: 10.1093/nar/17.7.2753.
• [13] Mutations of ventricular essential myosin light chain disturb myosin binding and sarcomeric sorting. Cardiovasc Res. 2012 Mar 1;93(3):390-6. doi: 10.1093/cvr/cvr320. Epub 2011 Nov 30.
• [14] 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.
• [15] Myosin light chain gene expression associated with disease states of the human heart.J Mol Cell Cardiol. 1993 May;25(5):577-85. doi: 10.1006/jmcc.1993.1067.
• [16] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [17] Functional cardiotoxicity assessment of cosmetic compounds using human-induced pluripotent stem cell-derived cardiomyocytes. Arch Toxicol. 2018 Jan;92(1):371-381.
• [18] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [19] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [20] 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.
• [21] 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.
• [22] 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.
• [23] 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.