Details of Drug Off-Target (DOT)

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

• DOT Name: Leiomodin-2 (LMOD2)
• Synonyms: Cardiac leiomodin; C-LMOD; Leiomodin
• Gene Name: LMOD2
• Related Disease:
  Cardiac failure
  Cardiomyopathy, dilated, 2G
  Congestive heart failure
  Dilated cardiomyopathy 1A
  Hypertrophic cardiomyopathy
  Psychotic disorder
  Schizophrenia
• UniProt ID: LMOD2_HUMAN
• PDB ID: 4RWT; 5WFN; 6UT2
• Pfam ID: PF03250
• Sequence:
  MSTFGYRRGLSKYESIDEDELLASLSAEELKELERELEDIEPDRNLPVGLRQKSLTEKTP
  TGTFSREALMAYWEKESQKLLEKERLGECGKVAEDKEESEEELIFTESNSEVSEEVYTEE
  EEEESQEEEEEEDSDEEERTIETAKGINGTVNYDSVNSDNSKPKIFKSQIENINLTNGSN
  GRNTESPAAIHPCGNPTVIEDALDKIKSNDPDTTEVNLNNIENITTQTLTRFAEALKDNT
  VVKTFSLANTHADDSAAMAIAEMLKVNEHITNVNVESNFITGKGILAIMRALQHNTVLTE
  LRFHNQRHIMGSQVEMEIVKLLKENTTLLRLGYHFELPGPRMSMTSILTRNMDKQRQKRL
  QEQKQQEGYDGGPNLRTKVWQRGTPSSSPYVSPRHSPWSSPKLPKKVQTVRSRPLSPVAT
  PPPPPPPPPPPPPSSQRLPPPPPPPPPPLPEKKLITRNIAEVIKQQESAQRALQNGQKKK
  KGKKVKKQPNSILKEIKNSLRSVQEKKMEDSSRPSTPQRSAHENLMEAIRGSSIKQLKRV
  EVPEALR
• Function: Mediates nucleation of actin filaments and thereby promotes actin polymerization. Plays a role in the regulation of actin filament length. Required for normal sarcomere organization in the heart, and for normal heart function.
• Tissue Specificity: Specifically expressed in heart and skeletal muscles, with higher levels in heart (at protein level). Not expressed in other tissues.
• KEGG Pathway: Cytoskeleton in muscle cells (hsa04820)

Molecular Interaction Atlas (MIA) of This DOT

7 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cardiac failure	DISDC067	Strong	Biomarker	[1]
Cardiomyopathy, dilated, 2G	DISSS40W	Strong	Autosomal recessive	[2]
Congestive heart failure	DIS32MEA	Strong	Biomarker	[1]
Dilated cardiomyopathy 1A	DIS0RK9Z	Strong	Genetic Variation	[3]
Hypertrophic cardiomyopathy	DISQG2AI	Strong	Genetic Variation	[3]
Psychotic disorder	DIS4UQOT	Strong	Biomarker	[4]
Schizophrenia	DISSRV2N	Strong	Biomarker	[4]

7 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 Leiomodin-2 (LMOD2).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Leiomodin-2 (LMOD2).	[6]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Leiomodin-2 (LMOD2).	[8]
Ethanol	DMDRQZU	Approved	Ethanol decreases the expression of Leiomodin-2 (LMOD2).	[9]
Clozapine	DMFC71L	Approved	Clozapine increases the expression of Leiomodin-2 (LMOD2).	[10]
Benzatropine	DMF7EXL	Approved	Benzatropine increases the expression of Leiomodin-2 (LMOD2).	[10]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Leiomodin-2 (LMOD2).	[12]

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 Leiomodin-2 (LMOD2).	[7]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Leiomodin-2 (LMOD2).	[11]

References

• [1] Cardiac-specific knockout of Lmod2 results in a severe reduction in myofilament force production and rapid cardiac failure.J Mol Cell Cardiol. 2018 Sep;122:88-97. doi: 10.1016/j.yjmcc.2018.08.009. Epub 2018 Aug 11.
• [2] Disruption of cardiac thin filament assembly arising from a mutation in LMOD2: A novel mechanism of neonatal dilated cardiomyopathy. Sci Adv. 2019 Sep 4;5(9):eaax2066. doi: 10.1126/sciadv.aax2066. eCollection 2019 Sep.
• [3] Effects of cardiomyopathy-linked mutations K15N and R21H in tropomyosin on thin-filament regulation and pointed-end dynamics.Mol Biol Cell. 2019 Jan 15;30(2):268-281. doi: 10.1091/mbc.E18-06-0406. Epub 2018 Nov 21.
• [4] Developmentally regulated and thalamus-selective induction of leiomodin2 gene by a schizophrenomimetic, phencyclidine, in the rat.Int J Neuropsychopharmacol. 2009 Sep;12(8):1111-26. doi: 10.1017/S1461145709009997. Epub 2009 Mar 2.
• [5] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [6] 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.
• [7] 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.
• [8] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [9] Cardiac toxicity from ethanol exposure in human-induced pluripotent stem cell-derived cardiomyocytes. Toxicol Sci. 2019 May 1;169(1):280-292.
• [10] Cannabidiol Displays Proteomic Similarities to Antipsychotics in Cuprizone-Exposed Human Oligodendrocytic Cell Line MO3.13. Front Mol Neurosci. 2021 May 28;14:673144. doi: 10.3389/fnmol.2021.673144. eCollection 2021.
• [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] 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.