Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTZ2MEMG)

• DOT Name: Leiomodin-1 (LMOD1)
• Synonyms: 64 kDa autoantigen 1D; 64 kDa autoantigen 1D3; 64 kDa autoantigen D1; Leiomodin, muscle form; Smooth muscle leiomodin; SM-Lmod; Thyroid-associated ophthalmopathy autoantigen
• Gene Name: LMOD1
• Related Disease:
  Arteriosclerosis
  Atherosclerosis
  Coronary atherosclerosis
  Coronary heart disease
  Esophageal squamous cell carcinoma
  Graves disease
  Hyperthyroidism
  Major depressive disorder
  Megacystis-microcolon-intestinal hypoperistalsis syndrome
  Mood disorder
  Progressive supranuclear palsy
  Sarcoidosis
  Smith-McCort dysplasia 1
  Colorectal carcinoma
  Type-1 diabetes
  Obsolete megacystis-microcolon-intestinal hypoperistalsis syndrome
  Endometriosis
  Trichohepatoenteric syndrome
  Leiomyosarcoma
  Megacystis-microcolon-intestinal hypoperistalsis syndrome 3
• UniProt ID: LMOD1_HUMAN
• PDB ID: 4Z79; 4Z8G; 4Z94
• Pfam ID: PF03250 ; PF02205
• Sequence:
  MSRVAKYRRQVSEDPDIDSLLETLSPEEMEELEKELDVVDPDGSVPVGLRQRNQTEKQST
  GVYNREAMLNFCEKETKKLMQREMSMDESKQVETKTDAKNGEERGRDASKKALGPRRDSD
  LGKEPKRGGLKKSFSRDRDEAGGKSGEKPKEEKIIRGIDKGRVRAAVDKKEAGKDGRGEE
  RAVATKKEEEKKGSDRNTGLSRDKDKKREEMKEVAKKEDDEKVKGERRNTDTRKEGEKMK
  RAGGNTDMKKEDEKVKRGTGNTDTKKDDEKVKKNEPLHEKEAKDDSKTKTPEKQTPSGPT
  KPSEGPAKVEEEAAPSIFDEPLERVKNNDPEMTEVNVNNSDCITNEILVRFTEALEFNTV
  VKLFALANTRADDHVAFAIAIMLKANKTITSLNLDSNHITGKGILAIFRALLQNNTLTEL
  RFHNQRHICGGKTEMEIAKLLKENTTLLKLGYHFELAGPRMTVTNLLSRNMDKQRQKRLQ
  EQRQAQEAKGEKKDLLEVPKAGAVAKGSPKPSPQPSPKPSPKNSPKKGGAPAAPPPPPPP
  LAPPLIMENLKNSLSPATQRKMGDKVLPAQEKNSRDQLLAAIRSSNLKQLKKVEVPKLLQ
• Function: Required for proper contractility of visceral smooth muscle cells. Mediates nucleation of actin filaments.
• Tissue Specificity: Detected in lung vascular smooth muscle (at protein level) . Detected in thyroid and extraocular smooth muscle, but not skeletal muscle . Detected in heart, aorta, skeletal muscle, colon, urinary bladder, uterus, stomach, and small intestine .
• KEGG Pathway: Cytoskeleton in muscle cells (hsa04820)
• Reactome Pathway: Smooth Muscle Contraction (R-HSA-445355)

Molecular Interaction Atlas (MIA) of This DOT

20 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Arteriosclerosis	DISK5QGC	Strong	Genetic Variation	[1]
Atherosclerosis	DISMN9J3	Strong	Genetic Variation	[1]
Coronary atherosclerosis	DISKNDYU	Strong	Genetic Variation	[2]
Coronary heart disease	DIS5OIP1	Strong	Genetic Variation	[3]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Biomarker	[4]
Graves disease	DISU4KOQ	Strong	Biomarker	[5]
Hyperthyroidism	DISX87ZH	Strong	Altered Expression	[6]
Major depressive disorder	DIS4CL3X	Strong	Genetic Variation	[7]
Megacystis-microcolon-intestinal hypoperistalsis syndrome	DIS9KV47	Strong	GermlineCausalMutation	[8]
Mood disorder	DISLVMWO	Strong	Genetic Variation	[7]
Progressive supranuclear palsy	DISO5KRQ	Strong	Biomarker	[9]
Sarcoidosis	DISE5B8Z	Strong	Genetic Variation	[10]
Smith-McCort dysplasia 1	DIS8072R	Strong	Biomarker	[2]
Colorectal carcinoma	DIS5PYL0	moderate	Biomarker	[11]
Type-1 diabetes	DIS7HLUB	moderate	Biomarker	[12]
Obsolete megacystis-microcolon-intestinal hypoperistalsis syndrome	DISP6WWH	Supportive	Autosomal dominant	[8]
Endometriosis	DISX1AG8	Disputed	Biomarker	[13]
Trichohepatoenteric syndrome	DISL3ODF	Disputed	Genetic Variation	[14]
Leiomyosarcoma	DIS6COXM	Limited	Biomarker	[15]
Megacystis-microcolon-intestinal hypoperistalsis syndrome 3	DISOB5GH	Limited	Unknown	[8]

12 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 Leiomodin-1 (LMOD1).	[16]
Estradiol	DMUNTE3	Approved	Estradiol affects the expression of Leiomodin-1 (LMOD1).	[17]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Leiomodin-1 (LMOD1).	[18]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Leiomodin-1 (LMOD1).	[13]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of Leiomodin-1 (LMOD1).	[20]
Dasatinib	DMJV2EK	Approved	Dasatinib increases the expression of Leiomodin-1 (LMOD1).	[21]
Permethrin	DMZ0Q1G	Approved	Permethrin decreases the expression of Leiomodin-1 (LMOD1).	[22]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Leiomodin-1 (LMOD1).	[23]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Leiomodin-1 (LMOD1).	[25]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Leiomodin-1 (LMOD1).	[26]
Deguelin	DMXT7WG	Investigative	Deguelin decreases the expression of Leiomodin-1 (LMOD1).	[27]
methyl p-hydroxybenzoate	DMO58UW	Investigative	methyl p-hydroxybenzoate increases the expression of Leiomodin-1 (LMOD1).	[28]

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 decreases the methylation of Leiomodin-1 (LMOD1).	[24]

References

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• [4] Identification of prothymosin alpha (PTMA) as a biomarker for esophageal squamous cell carcinoma (ESCC) by label-free quantitative proteomics and Quantitative Dot Blot (QDB).Clin Proteomics. 2019 Apr 5;16:12. doi: 10.1186/s12014-019-9232-6. eCollection 2019.
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• [6] Localization of the human 64kD autoantigen D1 to myofibrils in a subset of extraocular muscle fibers.Curr Eye Res. 1999 Oct;19(4):313-22. doi: 10.1076/ceyr.19.4.313.5304.
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• [8] Loss of LMOD1 impairs smooth muscle cytocontractility and causes megacystis microcolon intestinal hypoperistalsis syndrome in humans and mice. Proc Natl Acad Sci U S A. 2017 Mar 28;114(13):E2739-E2747. doi: 10.1073/pnas.1620507114. Epub 2017 Mar 14.
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• [10] Mycobacterial catalase-peroxidase is a tissue antigen and target of the adaptive immune response in systemic sarcoidosis.J Exp Med. 2005 Mar 7;201(5):755-67. doi: 10.1084/jem.20040429.
• [11] Identification of Potential Key Genes and Pathways in Early-Onset Colorectal Cancer Through Bioinformatics Analysis.Cancer Control. 2019 Jan-Dec;26(1):1073274819831260. doi: 10.1177/1073274819831260.
• [12] Antibodies to glutamic acid decarboxylase are associated with HLA-DR genotypes in both Australians and Asians with type 1 (insulin-dependent) diabetes mellitus.Diabetologia. 1992 Oct;35(10):996-1001. doi: 10.1007/BF00401432.
• [13] Unique transcriptome, pathways, and networks in the human endometrial fibroblast response to progesterone in endometriosis. Biol Reprod. 2011 Apr;84(4):801-15.
• [14] Homozygous deletion in MYL9 expands the molecular basis of megacystis-microcolon-intestinal hypoperistalsis syndrome.Eur J Hum Genet. 2018 May;26(5):669-675. doi: 10.1038/s41431-017-0055-5. Epub 2018 Feb 16.
• [15] Clinically Relevant Molecular Subtypes in Leiomyosarcoma.Clin Cancer Res. 2015 Aug 1;21(15):3501-11. doi: 10.1158/1078-0432.CCR-14-3141. Epub 2015 Apr 20.
• [16] 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.
• [17] Identification of novel low-dose bisphenol a targets in human foreskin fibroblast cells derived from hypospadias patients. PLoS One. 2012;7(5):e36711. doi: 10.1371/journal.pone.0036711. Epub 2012 May 4.
• [18] 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.
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• [21] Dasatinib reverses cancer-associated fibroblasts (CAFs) from primary lung carcinomas to a phenotype comparable to that of normal fibroblasts. Mol Cancer. 2010 Jun 27;9:168.
• [22] Exposure to Insecticides Modifies Gene Expression and DNA Methylation in Hematopoietic Tissues In Vitro. Int J Mol Sci. 2023 Mar 26;24(7):6259. doi: 10.3390/ijms24076259.
• [23] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
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• [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.
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