Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTB8URRI)

• DOT Name: Protein-glutamine gamma-glutamyltransferase K (TGM1)
• Synonyms: EC 2.3.2.13; Epidermal TGase; Transglutaminase K; TG(K); TGK; TGase K; Transglutaminase-1; TGase-1
• Gene Name: TGM1
• Related Disease:
  Autosomal recessive congenital ichthyosis 1
  Acral self-healing collodion baby
  Bathing suit ichthyosis
  Congenital ichthyosiform erythroderma
  Lamellar ichthyosis
  Self-healing collodion baby
• UniProt ID: TGM1_HUMAN
• PDB ID: 2XZZ
• EC Number: 2.3.2.13
• Pfam ID: PF00927 ; PF01841 ; PF00868
• Sequence:
  MMDGPRSDVGRWGGNPLQPPTTPSPEPEPEPDGRSRRGGGRSFWARCCGCCSCRNAADDD
  WGPEPSDSRGRGSSSGTRRPGSRGSDSRRPVSRGSGVNAAGDGTIREGMLVVNGVDLLSS
  RSDQNRREHHTDEYEYDELIVRRGQPFHMLLLLSRTYESSDRITLELLIGNNPEVGKGTH
  VIIPVGKGGSGGWKAQVVKASGQNLNLRVHTSPNAIIGKFQFTVRTQSDAGEFQLPFDPR
  NEIYILFNPWCPEDIVYVDHEDWRQEYVLNESGRIYYGTEAQIGERTWNYGQFDHGVLDA
  CLYILDRRGMPYGGRGDPVNVSRVISAMVNSLDDNGVLIGNWSGDYSRGTNPSAWVGSVE
  ILLSYLRTGYSVPYGQCWVFAGVTTTVLRCLGLATRTVTNFNSAHDTDTSLTMDIYFDEN
  MKPLEHLNHDSVWNFHVWNDCWMKRPDLPSGFDGWQVVDATPQETSSGIFCCGPCSVESI
  KNGLVYMKYDTPFIFAEVNSDKVYWQRQDDGSFKIVYVEEKAIGTLIVTKAISSNMREDI
  TYLYKHPEGSDAERKAVETAAAHGSKPNVYANRGSAEDVAMQVEAQDAVMGQDLMVSVML
  INHSSSRRTVKLHLYLSVTFYTGVSGTIFKETKKEVELAPGASDRVTMPVAYKEYRPHLV
  DQGAMLLNVSGHVKESGQVLAKQHTFRLRTPDLSLTLLGAAVVGQECEVQIVFKNPLPVT
  LTNVVFRLEGSGLQRPKILNVGDIGGNETVTLRQSFVPVRPGPRQLIASLDSPQLSQVHG
  VIQVDVAPAPGDGGFFSDAGGDSHLGETIPMASRGGA
• Function: Catalyzes the cross-linking of proteins and the conjugation of polyamines to proteins. Responsible for cross-linking epidermal proteins during formation of the stratum corneum. Involved in cell proliferation.
• Reactome Pathway: Formation of the cornified envelope (R-HSA-6809371)
• BioCyc Pathway: MetaCyc:HS01767-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

6 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Autosomal recessive congenital ichthyosis 1	DISWMIO6	Definitive	Autosomal recessive	[1]
Acral self-healing collodion baby	DISRL5X7	Supportive	Autosomal recessive	[2]
Bathing suit ichthyosis	DISWEBV5	Supportive	Autosomal recessive	[3]
Congenital ichthyosiform erythroderma	DISV8HQX	Supportive	Autosomal recessive	[4]
Lamellar ichthyosis	DIS714UN	Supportive	Autosomal recessive	[5]
Self-healing collodion baby	DIS1EEFN	Supportive	Autosomal recessive	[6]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Protein-glutamine gamma-glutamyltransferase K (TGM1).	[7]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Protein-glutamine gamma-glutamyltransferase K (TGM1).	[8]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Protein-glutamine gamma-glutamyltransferase K (TGM1).	[9]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Protein-glutamine gamma-glutamyltransferase K (TGM1).	[10]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Protein-glutamine gamma-glutamyltransferase K (TGM1).	[11]
Phenobarbital	DMXZOCG	Approved	Phenobarbital decreases the expression of Protein-glutamine gamma-glutamyltransferase K (TGM1).	[12]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of Protein-glutamine gamma-glutamyltransferase K (TGM1).	[13]
Alitretinoin	DMME8LH	Approved	Alitretinoin decreases the expression of Protein-glutamine gamma-glutamyltransferase K (TGM1).	[13]
Hydrocortisone	DMGEMB7	Approved	Hydrocortisone increases the expression of Protein-glutamine gamma-glutamyltransferase K (TGM1).	[14]
Bexarotene	DMOBIKY	Approved	Bexarotene decreases the expression of Protein-glutamine gamma-glutamyltransferase K (TGM1).	[15]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the expression of Protein-glutamine gamma-glutamyltransferase K (TGM1).	[16]
phorbol 12-myristate 13-acetate	DMJWD62	Phase 2	phorbol 12-myristate 13-acetate increases the expression of Protein-glutamine gamma-glutamyltransferase K (TGM1).	[14]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Protein-glutamine gamma-glutamyltransferase K (TGM1).	[17]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Protein-glutamine gamma-glutamyltransferase K (TGM1).	[18]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Protein-glutamine gamma-glutamyltransferase K (TGM1).	[19]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Protein-glutamine gamma-glutamyltransferase K (TGM1).	[20]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of Protein-glutamine gamma-glutamyltransferase K (TGM1).	[21]
all-trans-4-oxo-retinoic acid	DMM2R1N	Investigative	all-trans-4-oxo-retinoic acid decreases the expression of Protein-glutamine gamma-glutamyltransferase K (TGM1).	[13]
TTNPB	DMSABD0	Investigative	TTNPB decreases the expression of Protein-glutamine gamma-glutamyltransferase K (TGM1).	[15]
eucalyptol	DME5CK3	Investigative	eucalyptol decreases the expression of Protein-glutamine gamma-glutamyltransferase K (TGM1).	[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] Acral self-healing collodion baby: report of a new clinical phenotype caused by a novel TGM1 mutation. Br J Dermatol. 2009 Aug;161(2):456-63. doi: 10.1111/j.1365-2133.2009.09277.x. Epub 2009 Jun 4.
• [3] Bathing suit ichthyosis is caused by transglutaminase-1 deficiency: evidence for a temperature-sensitive phenotype. Hum Mol Genet. 2006 Nov 1;15(21):3083-97. doi: 10.1093/hmg/ddl249. Epub 2006 Sep 12.
• [4] The clinical spectrum of nonbullous congenital ichthyosiform erythroderma and lamellar ichthyosis. Clin Exp Dermatol. 2003 May;28(3):235-40. doi: 10.1046/j.1365-2230.2003.01295.x.
• [5] Inherited ichthyoses/generalized Mendelian disorders of cornification. Eur J Hum Genet. 2013 Feb;21(2):123-33. doi: 10.1038/ejhg.2012.121. Epub 2012 Jun 27.
• [6] Self-healing collodion baby: a dynamic phenotype explained by a particular transglutaminase-1 mutation. J Invest Dermatol. 2003 Feb;120(2):224-8. doi: 10.1046/j.1523-1747.2003.12032.x.
• [7] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [8] Retinoic acid receptors as regulators of human epidermal keratinocyte differentiation. Mol Endocrinol. 1992 May;6(5):667-76. doi: 10.1210/mend.6.5.1318502.
• [9] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [10] Research resource: STR DNA profile and gene expression comparisons of human BG-1 cells and a BG-1/MCF-7 clonal variant. Mol Endocrinol. 2014 Dec;28(12):2072-81.
• [11] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [12] Proteomic analysis of hepatic effects of phenobarbital in mice with humanized liver. Arch Toxicol. 2022 Oct;96(10):2739-2754. doi: 10.1007/s00204-022-03338-7. Epub 2022 Jul 26.
• [13] Retinoic acid and its 4-oxo metabolites are functionally active in human skin cells in vitro. J Invest Dermatol. 2005 Jul;125(1):143-53.
• [14] Keratinocyte differentiation marker suppression by arsenic: mediation by AP1 response elements and antagonism by tetradecanoylphorbol acetate. Toxicol Appl Pharmacol. 2001 Aug 1;174(3):302-11.
• [15] Retinoic acid receptor- and retinoid X receptor-selective retinoids activate signaling pathways that converge on AP-1 and inhibit squamous differentiation in human bronchial epithelial cells. Cell Growth Differ. 1996 Aug;7(8):997-1004.
• [16] Differentiation-specific factors modulate epidermal CYP1-4 gene expression in human skin in response to retinoic acid and classic aryl hydrocarbon receptor ligands. J Pharmacol Exp Ther. 2006 Dec;319(3):1162-71.
• [17] Effect of benzo[a]pyrene on proliferation and metastasis of oral squamous cell carcinoma cells: A transcriptome analysis based on RNA-seq. Environ Toxicol. 2022 Nov;37(11):2589-2604. doi: 10.1002/tox.23621. Epub 2022 Jul 23.
• [18] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [19] Comparative Analysis of Transcriptomic Changes including mRNA and microRNA Expression Induced by the Xenoestrogens Zearalenone and Bisphenol A in Human Ovarian Cells. Toxins (Basel). 2023 Feb 9;15(2):140. doi: 10.3390/toxins15020140.
• [20] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [21] 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.
• [22] Transcriptome Analysis Reveals the Anti-Tumor Mechanism of Eucalyptol Treatment on Neuroblastoma Cell Line SH-SY5Y. Neurochem Res. 2022 Dec;47(12):3854-3862. doi: 10.1007/s11064-022-03786-8. Epub 2022 Nov 4.