Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTC58V2Q)

• DOT Name: Myosin light chain kinase 3 (MYLK3)
• Synonyms: EC 2.7.11.18; Cardiac-MyBP-C-associated Ca/CaM kinase; Cardiac-MLCK
• Gene Name: MYLK3
• Related Disease:
  Cardiac failure
  Colitis
  Congestive heart failure
  Constipation
  Crohn disease
  Dilated cardiomyopathy 1A
  Epithelial ovarian cancer
  Familial dilated cardiomyopathy
  Inflammatory bowel disease
  Irritable bowel syndrome
  Ovarian cancer
  Ovarian neoplasm
  Superficial epidermolytic ichthyosis
  Leiomyosarcoma
• UniProt ID: MYLK3_HUMAN
• EC Number: 2.7.11.18
• Pfam ID: PF00069
• Sequence:
  MSGTSKESLGHGGLPGLGKTCLTTMDTKLNMLNEKVDQLLHFQEDVTEKLQSMCRDMGHL
  ERGLHRLEASRAPGPGGADGVPHIDTQAGWPEVLELVRAMQQDAAQHGARLEALFRMVAA
  VDRAIALVGATFQKSKVADFLMQGRVPWRRGSPGDSPEENKERVEEEGGKPKHVLSTSGV
  QSDAREPGEESQKADVLEGTAERLPPIRASGLGADPAQAVVSPGQGDGVPGPAQAFPGHL
  PLPTKVEAKAPETPSENLRTGLELAPAPGRVNVVSPSLEVAPGAGQGASSSRPDPEPLEE
  GTRLTPGPGPQCPGPPGLPAQARATHSGGETPPRISIHIQEMDTPGEMLMTGRGSLGPTL
  TTEAPAAAQPGKQGPPGTGRCLQAPGTEPGEQTPEGARELSPLQESSSPGGVKAEEEQRA
  GAEPGTRPSLARSDDNDHEVGALGLQQGKSPGAGNPEPEQDCAARAPVRAEAVRRMPPGA
  EAGSVVLDDSPAPPAPFEHRVVSVKETSISAGYEVCQHEVLGGGRFGQVHRCTEKSTGLP
  LAAKIIKVKSAKDREDVKNEINIMNQLSHVNLIQLYDAFESKHSCTLVMEYVDGGELFDR
  ITDEKYHLTELDVVLFTRQICEGVHYLHQHYILHLDLKPENILCVNQTGHQIKIIDFGLA
  RRYKPREKLKVNFGTPEFLAPEVVNYEFVSFPTDMWSVGVITYMLLSGLSPFLGETDAET
  MNFIVNCSWDFDADTFEGLSEEAKDFVSRLLVKEKSCRMSATQCLKHEWLNNLPAKASRS
  KTRLKSQLLLQKYIAQRKWKKHFYVVTAANRLRKFPTSP
• Function: Kinase that phosphorylates MYL2 in vitro. Promotes sarcomere formation in cardiomyocytes and increases cardiomyocyte contractility.
• Tissue Specificity: Restricted to heart.
• KEGG Pathway:
  Calcium sig.ling pathway (hsa04020)
  cGMP-PKG sig.ling pathway (hsa04022)
  Vascular smooth muscle contraction (hsa04270)
  Apelin sig.ling pathway (hsa04371)
  Focal adhesion (hsa04510)
  Platelet activation (hsa04611)
  Regulation of actin cytoskeleton (hsa04810)
  Oxytocin sig.ling pathway (hsa04921)
  Gastric acid secretion (hsa04971)

Molecular Interaction Atlas (MIA) of This DOT

14 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cardiac failure	DISDC067	Strong	Genetic Variation	[1]
Colitis	DISAF7DD	Strong	Altered Expression	[2]
Congestive heart failure	DIS32MEA	Strong	Genetic Variation	[1]
Constipation	DISRQXWI	Strong	Altered Expression	[3]
Crohn disease	DIS2C5Q8	Strong	Biomarker	[4]
Dilated cardiomyopathy 1A	DIS0RK9Z	Strong	Genetic Variation	[1]
Epithelial ovarian cancer	DIS56MH2	Strong	Biomarker	[5]
Familial dilated cardiomyopathy	DISBHDU9	Strong	Genetic Variation	[1]
Inflammatory bowel disease	DISGN23E	Strong	Altered Expression	[6]
Irritable bowel syndrome	DIS27206	Strong	Biomarker	[7]
Ovarian cancer	DISZJHAP	Strong	Biomarker	[5]
Ovarian neoplasm	DISEAFTY	Strong	Biomarker	[5]
Superficial epidermolytic ichthyosis	DISWX6O4	Strong	Biomarker	[7]
Leiomyosarcoma	DIS6COXM	Limited	Biomarker	[8]

3 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 Myosin light chain kinase 3 (MYLK3).	[9]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Myosin light chain kinase 3 (MYLK3).	[10]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of Myosin light chain kinase 3 (MYLK3).	[13]

3 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 Myosin light chain kinase 3 (MYLK3).	[11]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Myosin light chain kinase 3 (MYLK3).	[12]
Microcystin-LR	DMTMLRN	Investigative	Microcystin-LR decreases the methylation of Myosin light chain kinase 3 (MYLK3).	[14]

References

• [1] Identification of MYLK3 mutations in familial dilated cardiomyopathy.Sci Rep. 2017 Dec 13;7(1):17495. doi: 10.1038/s41598-017-17769-1.
• [2] Aryl Hydrocarbon Receptor Activation Modulates Intestinal Epithelial Barrier Function by Maintaining Tight Junction Integrity.Int J Biol Sci. 2018 Jan 11;14(1):69-77. doi: 10.7150/ijbs.22259. eCollection 2018.
• [3] Ardipusilloside-I stimulates gastrointestinal motility and phosphorylation of smooth muscle myosin by myosin light chain kinase.Korean J Physiol Pharmacol. 2017 Nov;21(6):609-616. doi: 10.4196/kjpp.2017.21.6.609. Epub 2017 Oct 30.
• [4] Herbs-partitioned moxibustion improves intestinal epithelial tight junctions by upregulating A20 expression in a mouse model of Crohn's disease.Biomed Pharmacother. 2019 Oct;118:109149. doi: 10.1016/j.biopha.2019.109149. Epub 2019 Jul 12.
• [5] Methylation of MYLK3 gene promoter region: a biomarker to stratify surgical care in ovarian cancer in a multicentre study.Br J Cancer. 2017 May 9;116(10):1287-1293. doi: 10.1038/bjc.2017.83. Epub 2017 Mar 28.
• [6] CCAT1 lncRNA Promotes Inflammatory Bowel Disease Malignancy by Destroying Intestinal Barrier via Downregulating miR-185-3p.Inflamm Bowel Dis. 2019 Apr 11;25(5):862-874. doi: 10.1093/ibd/izy381.
• [7] MLCK-mediated intestinal permeability promotes immune activation and visceral hypersensitivity in PI-IBS mice.Neurogastroenterol Motil. 2018 Sep;30(9):e13348. doi: 10.1111/nmo.13348. Epub 2018 Apr 11.
• [8] Myosin regulatory light chain phosphorylation is associated with leiomyosarcoma development.Biomed Pharmacother. 2017 Aug;92:810-818. doi: 10.1016/j.biopha.2017.05.139. Epub 2017 Jun 10.
• [9] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [10] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [11] 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.
• [12] 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.
• [13] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.
• [14] Gene expression network regulated by DNA methylation and microRNA during microcystin-leucine arginine induced malignant transformation in human hepatocyte L02 cells. Toxicol Lett. 2018 Jun 1;289:42-53. doi: 10.1016/j.toxlet.2018.03.003. Epub 2018 Mar 5.