Details of Drug Off-Target (DOT)

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

• DOT Name: Myosin light chain 4 (MYL4)
• Synonyms: Myosin light chain 1, embryonic muscle/atrial isoform; Myosin light chain alkali GT-1 isoform
• Gene Name: MYL4
• Related Disease:
  Congenital anomaly of kidney and urinary tract
  Parkinson disease
  Atrial fibrillation, familial, 18
  Breast cancer
  Breast carcinoma
  Cardiac disease
  Cardiac failure
  Chromosomal disorder
  Congenital heart disease
  Congestive heart failure
  Esophageal squamous cell carcinoma
  Hypertrophic cardiomyopathy
  Tetralogy of fallot
  Familial atrial fibrillation
  Atrial fibrillation
• UniProt ID: MYL4_HUMAN
• Sequence:
  MAPKKPEPKKEAAKPAPAPAPAPAPAPAPAPEAPKEPAFDPKSVKIDFTADQIEEFKEAF
  SLFDRTPTGEMKITYGQCGDVLRALGQNPTNAEVLRVLGKPKPEEMNVKMLDFETFLPIL
  QHISRNKEQGTYEDFVEGLRVFDKESNGTVMGAELRHVLATLGEKMTEAEVEQLLAGQED
  ANGCINYEAFVKHIMSG
• 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)
• Reactome Pathway: Striated Muscle Contraction (R-HSA-390522)

Molecular Interaction Atlas (MIA) of This DOT

15 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Congenital anomaly of kidney and urinary tract	DIS84IVH	Definitive	Genetic Variation	[1]
Parkinson disease	DISQVHKL	Definitive	Biomarker	[2]
Atrial fibrillation, familial, 18	DISON7YO	Strong	Autosomal dominant	[3]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[4]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[4]
Cardiac disease	DISVO1I5	Strong	Genetic Variation	[5]
Cardiac failure	DISDC067	Strong	Altered Expression	[6]
Chromosomal disorder	DISM5BB5	Strong	Biomarker	[7]
Congenital heart disease	DISQBA23	Strong	Altered Expression	[6]
Congestive heart failure	DIS32MEA	Strong	Altered Expression	[6]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Biomarker	[8]
Hypertrophic cardiomyopathy	DISQG2AI	moderate	Altered Expression	[9]
Tetralogy of fallot	DISMHFNW	moderate	Biomarker	[10]
Familial atrial fibrillation	DISL4AGF	Supportive	Autosomal dominant	[3]
Atrial fibrillation	DIS15W6U	Limited	Genetic Variation	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Myosin light chain 4 (MYL4).	[12]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Myosin light chain 4 (MYL4).	[13]
Doxorubicin	DMVP5YE	Approved	Doxorubicin affects the expression of Myosin light chain 4 (MYL4).	[14]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Myosin light chain 4 (MYL4).	[16]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Myosin light chain 4 (MYL4).	[17]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Myosin light chain 4 (MYL4).	[18]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil decreases the expression of Myosin light chain 4 (MYL4).	[19]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of Myosin light chain 4 (MYL4).	[20]
Cytarabine	DMZD5QR	Approved	Cytarabine decreases the expression of Myosin light chain 4 (MYL4).	[21]
Capsaicin	DMGMF6V	Approved	Capsaicin decreases the expression of Myosin light chain 4 (MYL4).	[22]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of Myosin light chain 4 (MYL4).	[23]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Myosin light chain 4 (MYL4).	[25]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Myosin light chain 4 (MYL4).	[26]
Deguelin	DMXT7WG	Investigative	Deguelin decreases the expression of Myosin light chain 4 (MYL4).	[22]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Myosin light chain 4 (MYL4).	[15]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Myosin light chain 4 (MYL4).	[24]

References

• [1] CHD1L: a new candidate gene for congenital anomalies of the kidneys and urinary tract (CAKUT).Nephrol Dial Transplant. 2012 Jun;27(6):2355-64. doi: 10.1093/ndt/gfr649. Epub 2011 Dec 6.
• [2] Progression Rate Associated Peripheral Blood Biomarkers of Parkinson's Disease.J Mol Neurosci. 2018 Jul;65(3):312-318. doi: 10.1007/s12031-018-1102-6. Epub 2018 Jun 23.
• [3] A mutation in the atrial-specific myosin light chain gene (MYL4) causes familial atrial fibrillation. Nat Commun. 2016 Apr 12;7:11303. doi: 10.1038/ncomms11303.
• [4] Poly(ADPribose) polymerase 1/2 inhibitors decrease the ubiquitination of ALC1 mediated by CHFR in breast cancer.Oncol Rep. 2019 Oct;42(4):1467-1474. doi: 10.3892/or.2019.7242. Epub 2019 Jul 18.
• [5] Rs4968309 in Myosin Light Chain 4 (MYL4) Associated With Atrial Fibrillation Onset and Predicts Clinical Outcomes After Catheter Ablation in Atrial Fibrillation Patients Without Structural Heart Disease.Circ J. 2019 Sep 25;83(10):1994-2001. doi: 10.1253/circj.CJ-19-0415. Epub 2019 Aug 10.
• [6] 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.
• [7] Chromatin remodeler ALC1 prevents replication-fork collapse by slowing fork progression.PLoS One. 2018 Feb 6;13(2):e0192421. doi: 10.1371/journal.pone.0192421. eCollection 2018.
• [8] ALC1 knockdown enhances cisplatin cytotoxicity of esophageal squamous cell carcinoma cells by inhibition of glycolysis through PI3K/Akt pathway.Life Sci. 2019 Sep 1;232:116679. doi: 10.1016/j.lfs.2019.116679. Epub 2019 Jul 21.
• [9] Human cardiac myosin light chain 4 (MYL4) mosaic expression patterns vary by sex.Sci Rep. 2019 Sep 3;9(1):12681. doi: 10.1038/s41598-019-49191-0.
• [10] Remodeling of the hypertrophied human myocardium by cardiac bHLH transcription factors.J Cell Biochem. 1999 Sep 15;74(4):551-61. doi: 10.1002/(sici)1097-4644(19990915)74:4<551::aid-jcb5>3.3.co;2-0.
• [11] Metastable Atrial State Underlies the Primary Genetic Substrate for MYL4 Mutation-Associated Atrial Fibrillation.Circulation. 2020 Jan 28;141(4):301-312. doi: 10.1161/CIRCULATIONAHA.119.044268. Epub 2019 Nov 16.
• [12] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [13] 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.
• [14] 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.
• [15] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [16] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [17] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [18] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [19] Evaluation of developmental toxicity using undifferentiated human embryonic stem cells. J Appl Toxicol. 2015 Feb;35(2):205-18.
• [20] Temporal changes in gene expression in the skin of patients treated with isotretinoin provide insight into its mechanism of action. Dermatoendocrinol. 2009 May;1(3):177-87.
• [21] Cytosine arabinoside induces ectoderm and inhibits mesoderm expression in human embryonic stem cells during multilineage differentiation. Br J Pharmacol. 2011 Apr;162(8):1743-56.
• [22] Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors. Arch Toxicol. 2021 Feb;95(2):591-615. doi: 10.1007/s00204-020-02970-5. Epub 2021 Jan 29.
• [23] Identification by automated screening of a small molecule that selectively eliminates neural stem cells derived from hESCs but not dopamine neurons. PLoS One. 2009 Sep 23;4(9):e7155.
• [24] 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.
• [25] 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.
• [26] Low doses of BPA induced abnormal mitochondrial fission and hypertrophy in human embryonic stem cell-derived cardiomyocytes via the calcineurin-DRP1 signaling pathway: A comparison between XX and XY cardiomyocytes. Toxicol Appl Pharmacol. 2020 Feb 1;388:114850. doi: 10.1016/j.taap.2019.114850. Epub 2019 Dec 9.