Details of Drug Off-Target (DOT)

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

• DOT Name: Protein-glutamine gamma-glutamyltransferase E (TGM3)
• Synonyms: EC 2.3.2.13; Transglutaminase E; TG(E); TGE; TGase E; Transglutaminase-3; TGase-3
• Gene Name: TGM3
• Related Disease: Uncombable hair syndrome
• UniProt ID: TGM3_HUMAN
• PDB ID: 1L9M; 1L9N; 1NUD; 1NUF; 1NUG; 8OXV; 8OXW; 8OXX; 8OXY
• EC Number: 2.3.2.13
• Pfam ID: PF00927 ; PF01841 ; PF00868
• Sequence:
  MAALGVQSINWQTAFNRQAHHTDKFSSQELILRRGQNFQVLMIMNKGLGSNERLEFIVST
  GPYPSESAMTKAVFPLSNGSSGGWSAVLQASNGNTLTISISSPASAPIGRYTMALQIFSQ
  GGISSVKLGTFILLFNPWLNVDSVFMGNHAEREEYVQEDAGIIFVGSTNRIGMIGWNFGQ
  FEEDILSICLSILDRSLNFRRDAATDVASRNDPKYVGRVLSAMINSNDDNGVLAGNWSGT
  YTGGRDPRSWNGSVEILKNWKKSGFSPVRYGQCWVFAGTLNTALRSLGIPSRVITNFNSA
  HDTDRNLSVDVYYDPMGNPLDKGSDSVWNFHVWNEGWFVRSDLGPSYGGWQVLDATPQER
  SQGVFQCGPASVIGVREGDVQLNFDMPFIFAEVNADRITWLYDNTTGKQWKNSVNSHTIG
  RYISTKAVGSNARMDVTDKYKYPEGSDQERQVFQKALGKLKPNTPFAATSSMGLETEEQE
  PSIIGKLKVAGMLAVGKEVNLVLLLKNLSRDTKTVTVNMTAWTIIYNGTLVHEVWKDSAT
  MSLDPEEEAEHPIKISYAQYEKYLKSDNMIRITAVCKVPDESEVVVERDIILDNPTLTLE
  VLNEARVRKPVNVQMLFSNPLDEPVRDCVLMVEGSGLLLGNLKIDVPTLGPKEGSRVRFD
  ILPSRSGTKQLLADFSCNKFPAIKAMLSIDVAE
• Function: Catalyzes the calcium-dependent formation of isopeptide cross-links between glutamine and lysine residues in various proteins, as well as the conjugation of polyamines to proteins. Involved in the formation of the cornified envelope (CE), a specialized component consisting of covalent cross-links of proteins beneath the plasma membrane of terminally differentiated keratinocytes. Catalyzes small proline-rich proteins (SPRR1 and SPRR2) and LOR cross-linking to form small interchain oligomers, which are further cross-linked by TGM1 onto the growing CE scaffold. In hair follicles, involved in cross-linking structural proteins to hardening the inner root sheath.

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Uncombable hair syndrome	DISJNMLZ	Supportive	Autosomal recessive	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Protein-glutamine gamma-glutamyltransferase E (TGM3).	[2]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Protein-glutamine gamma-glutamyltransferase E (TGM3).	[2]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the expression of Protein-glutamine gamma-glutamyltransferase E (TGM3).	[3]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Protein-glutamine gamma-glutamyltransferase E (TGM3).	[5]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Protein-glutamine gamma-glutamyltransferase E (TGM3).	[6]

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 affects the methylation of Protein-glutamine gamma-glutamyltransferase E (TGM3).	[4]

References

• [1] Mutations in Three Genes Encoding Proteins Involved in Hair Shaft Formation Cause Uncombable Hair Syndrome. Am J Hum Genet. 2016 Dec 1;99(6):1292-1304. doi: 10.1016/j.ajhg.2016.10.004. Epub 2016 Nov 17.
• [2] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [3] 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.
• [4] 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.
• [5] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [6] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.