Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT6MFOWF)

• DOT Name: Protein-glutamine gamma-glutamyltransferase 2 (TGM2)
• Synonyms: EC 2.3.2.13; Erythrocyte transglutaminase; Heart G alpha(h); hhG alpha(h); Isopeptidase TGM2; EC 3.4.-.-; Protein G alpha(h); G(h); Protein-glutamine deamidase TGM2; EC 3.5.1.44; Protein-glutamine dopaminyltransferase TGM2; EC 2.3.1.-; Protein-glutamine histaminyltransferase TGM2; EC 2.3.1.-; Protein-glutamine noradrenalinyltransferase TGM2; EC 2.3.1.-; Protein-glutamine serotonyltransferase TGM2; EC 2.3.1.-; Tissue transglutaminase; tTG; tTgase; Transglutaminase C; TG(C); TGC; TGase C; Transglutaminase H; TGase H; Transglutaminase II; TGase II; Transglutaminase-2; TG2; TGase-2; hTG2
• Gene Name: TGM2
• Related Disease: Non-insulin dependent diabetes
• UniProt ID: TGM2_HUMAN
• PDB ID: 1KV3; 2Q3Z; 3LY6; 3S3J; 3S3P; 3S3S; 4PYG; 6A8P; 6KZB
• EC Number: 2.3.1.-; 2.3.2.13; 3.4.-.-; 3.5.1.44
• Pfam ID: PF00927 ; PF01841 ; PF00868
• Sequence:
  MAEELVLERCDLELETNGRDHHTADLCREKLVVRRGQPFWLTLHFEGRNYEASVDSLTFS
  VVTGPAPSQEAGTKARFPLRDAVEEGDWTATVVDQQDCTLSLQLTTPANAPIGLYRLSLE
  ASTGYQGSSFVLGHFILLFNAWCPADAVYLDSEEERQEYVLTQQGFIYQGSAKFIKNIPW
  NFGQFEDGILDICLILLDVNPKFLKNAGRDCSRRSSPVYVGRVVSGMVNCNDDQGVLLGR
  WDNNYGDGVSPMSWIGSVDILRRWKNHGCQRVKYGQCWVFAAVACTVLRCLGIPTRVVTN
  YNSAHDQNSNLLIEYFRNEFGEIQGDKSEMIWNFHCWVESWMTRPDLQPGYEGWQALDPT
  PQEKSEGTYCCGPVPVRAIKEGDLSTKYDAPFVFAEVNADVVDWIQQDDGSVHKSINRSL
  IVGLKISTKSVGRDEREDITHTYKYPEGSSEEREAFTRANHLNKLAEKEETGMAMRIRVG
  QSMNMGSDFDVFAHITNNTAEEYVCRLLLCARTVSYNGILGPECGTKYLLNLNLEPFSEK
  SVPLCILYEKYRDCLTESNLIKVRALLVEPVINSYLLAERDLYLENPEIKIRILGEPKQK
  RKLVAEVSLQNPLPVALEGCTFTVEGAGLTEEQKTVEIPDPVEAGEEVKVRMDLLPLHMG
  LHKLVVNFESDKLKAVKGFRNVIIGPA
• Function: Calcium-dependent acyltransferase that catalyzes the formation of covalent bonds between peptide-bound glutamine and various primary amines, such as gamma-amino group of peptide-bound lysine, or mono- and polyamines, thereby producing cross-linked or aminated proteins, respectively. Involved in many biological processes, such as bone development, angiogenesis, wound healing, cellular differentiation, chromatin modification and apoptosis. Acts as a protein-glutamine gamma-glutamyltransferase by mediating the cross-linking of proteins, such as ACO2, HSPB6, FN1, HMGB1, RAP1GDS1, SLC25A4/ANT1, SPP1 and WDR54. Under physiological conditions, the protein cross-linking activity is inhibited by GTP; inhibition is relieved by Ca(2+) in response to various stresses. When secreted, catalyzes cross-linking of proteins of the extracellular matrix, such as FN1 and SPP1 resulting in the formation of scaffolds. Plays a key role during apoptosis, both by (1) promoting the cross-linking of cytoskeletal proteins resulting in condensation of the cytoplasm, and by (2) mediating cross-linking proteins of the extracellular matrix, resulting in the irreversible formation of scaffolds that stabilize the integrity of the dying cells before their clearance by phagocytosis, thereby preventing the leakage of harmful intracellular components. In addition to protein cross-linking, can use different monoamine substrates to catalyze a vast array of protein post-translational modifications: mediates aminylation of serotonin, dopamine, noradrenaline or histamine into glutamine residues of target proteins to generate protein serotonylation, dopaminylation, noradrenalinylation or histaminylation, respectively. Mediates protein serotonylation of small GTPases during activation and aggregation of platelets, leading to constitutive activation of these GTPases. Plays a key role in chromatin organization by mediating serotonylation and dopaminylation of histone H3. Catalyzes serotonylation of 'Gln-5' of histone H3 (H3Q5ser) during serotonergic neuron differentiation, thereby facilitating transcription. Acts as a mediator of neurotransmission-independent role of nuclear dopamine in ventral tegmental area (VTA) neurons: catalyzes dopaminylation of 'Gln-5' of histone H3 (H3Q5dop), thereby regulating relapse-related transcriptional plasticity in the reward system. Regulates vein remodeling by mediating serotonylation and subsequent inactivation of ATP2A2/SERCA2. Also acts as a protein deamidase by mediating the side chain deamidation of specific glutamine residues of proteins to glutamate. Catalyzes specific deamidation of protein gliadin, a component of wheat gluten in the diet. May also act as an isopeptidase cleaving the previously formed cross-links. Also able to participate in signaling pathways independently of its acyltransferase activity: acts as a signal transducer in alpha-1 adrenergic receptor-mediated stimulation of phospholipase C-delta (PLCD) activity and is required for coupling alpha-1 adrenergic agonists to the stimulation of phosphoinositide lipid metabolism ; [Isoform 2]: Has cytotoxic activity: is able to induce apoptosis independently of its acyltransferase activity.
• KEGG Pathway: Huntington disease (hsa05016)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Non-insulin dependent diabetes	DISK1O5Z	Limited	Autosomal dominant	[1]

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Mitomycin	DMH0ZJE	Approved	Protein-glutamine gamma-glutamyltransferase 2 (TGM2) affects the response to substance of Mitomycin.	[34]
Topotecan	DMP6G8T	Approved	Protein-glutamine gamma-glutamyltransferase 2 (TGM2) affects the response to substance of Topotecan.	[34]

2 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Protein-glutamine gamma-glutamyltransferase 2 (TGM2).	[2]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Protein-glutamine gamma-glutamyltransferase 2 (TGM2).	[24]

34 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 2 (TGM2).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Protein-glutamine gamma-glutamyltransferase 2 (TGM2).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Protein-glutamine gamma-glutamyltransferase 2 (TGM2).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Protein-glutamine gamma-glutamyltransferase 2 (TGM2).	[6]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Protein-glutamine gamma-glutamyltransferase 2 (TGM2).	[7]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Protein-glutamine gamma-glutamyltransferase 2 (TGM2).	[8]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Protein-glutamine gamma-glutamyltransferase 2 (TGM2).	[9]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Protein-glutamine gamma-glutamyltransferase 2 (TGM2).	[10]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Protein-glutamine gamma-glutamyltransferase 2 (TGM2).	[10]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Protein-glutamine gamma-glutamyltransferase 2 (TGM2).	[11]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Protein-glutamine gamma-glutamyltransferase 2 (TGM2).	[12]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Protein-glutamine gamma-glutamyltransferase 2 (TGM2).	[13]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone increases the expression of Protein-glutamine gamma-glutamyltransferase 2 (TGM2).	[14]
Ethanol	DMDRQZU	Approved	Ethanol increases the expression of Protein-glutamine gamma-glutamyltransferase 2 (TGM2).	[15]
Piroxicam	DMTK234	Approved	Piroxicam decreases the expression of Protein-glutamine gamma-glutamyltransferase 2 (TGM2).	[16]
Alitretinoin	DMME8LH	Approved	Alitretinoin increases the expression of Protein-glutamine gamma-glutamyltransferase 2 (TGM2).	[17]
Beta-carotene	DM0RXBT	Approved	Beta-carotene increases the expression of Protein-glutamine gamma-glutamyltransferase 2 (TGM2).	[18]
Bexarotene	DMOBIKY	Approved	Bexarotene increases the expression of Protein-glutamine gamma-glutamyltransferase 2 (TGM2).	[19]
Etretinate	DM2CZFA	Approved	Etretinate increases the expression of Protein-glutamine gamma-glutamyltransferase 2 (TGM2).	[20]
Vitamin A	DMJ2AH4	Approved	Vitamin A increases the expression of Protein-glutamine gamma-glutamyltransferase 2 (TGM2).	[18]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Protein-glutamine gamma-glutamyltransferase 2 (TGM2).	[21]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene increases the activity of Protein-glutamine gamma-glutamyltransferase 2 (TGM2).	[22]
PD-0325901	DM27D4J	Phase 2	PD-0325901 decreases the expression of Protein-glutamine gamma-glutamyltransferase 2 (TGM2).	[23]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Protein-glutamine gamma-glutamyltransferase 2 (TGM2).	[25]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Protein-glutamine gamma-glutamyltransferase 2 (TGM2).	[26]
PMID27336223-Compound-5	DM6E50A	Patented	PMID27336223-Compound-5 increases the expression of Protein-glutamine gamma-glutamyltransferase 2 (TGM2).	[14]
PMID26560530-Compound-8	DMN6TG7	Patented	PMID26560530-Compound-8 decreases the activity of Protein-glutamine gamma-glutamyltransferase 2 (TGM2).	[27]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Protein-glutamine gamma-glutamyltransferase 2 (TGM2).	[28]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Protein-glutamine gamma-glutamyltransferase 2 (TGM2).	[29]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Protein-glutamine gamma-glutamyltransferase 2 (TGM2).	[30]
QUERCITRIN	DM1DH96	Investigative	QUERCITRIN decreases the expression of Protein-glutamine gamma-glutamyltransferase 2 (TGM2).	[31]
all-trans-4-oxo-retinoic acid	DMM2R1N	Investigative	all-trans-4-oxo-retinoic acid increases the expression of Protein-glutamine gamma-glutamyltransferase 2 (TGM2).	[18]
Chlorphrifos oxon	DMGBT68	Investigative	Chlorphrifos oxon increases the activity of Protein-glutamine gamma-glutamyltransferase 2 (TGM2).	[32]
TTNPB	DMSABD0	Investigative	TTNPB increases the expression of Protein-glutamine gamma-glutamyltransferase 2 (TGM2).	[4]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Guanosine-5'-Triphosphate	DMV2OJX	Investigative	Guanosine-5'-Triphosphate affects the binding of Protein-glutamine gamma-glutamyltransferase 2 (TGM2).	[33]

References

• [1] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [2] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [3] Inter-laboratory comparison of human renal proximal tubule (HK-2) transcriptome alterations due to Cyclosporine A exposure and medium exhaustion. Toxicol In Vitro. 2009 Apr;23(3):486-99.
• [4] TCDD suppression of tissue transglutaminase stimulation by retinoids in malignant human keratinocytes. Toxicol Sci. 2000 Aug;56(2):357-64.
• [5] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [6] Two distinct modes of cell death induced by doxorubicin: apoptosis and cell death through mitotic catastrophe accompanied by senescence-like phenotype. Oncogene. 2005 Jul 14;24(30):4765-77.
• [7] Long-term estrogen exposure promotes carcinogen bioactivation, induces persistent changes in gene expression, and enhances the tumorigenicity of MCF-7 human breast cancer cells. Toxicol Appl Pharmacol. 2009 Nov 1;240(3):355-66.
• [8] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [9] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [10] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [11] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [12] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [13] Endometrial receptivity is affected in women with high circulating progesterone levels at the end of the follicular phase: a functional genomics analysis. Hum Reprod. 2011 Jul;26(7):1813-25.
• [14] PPARgamma controls CD1d expression by turning on retinoic acid synthesis in developing human dendritic cells. J Exp Med. 2006 Oct 2;203(10):2351-62.
• [15] NF-kappaB-activated tissue transglutaminase is involved in ethanol-induced hepatic injury and the possible role of propolis in preventing fibrogenesis. Toxicology. 2008 Apr 18;246(2-3):148-57.
• [16] Apoptosis induced by piroxicam plus cisplatin combined treatment is triggered by p21 in mesothelioma. PLoS One. 2011;6(8):e23569.
• [17] Arginine methylation provides epigenetic transcription memory for retinoid-induced differentiation in myeloid cells. Mol Cell Biol. 2005 Jul;25(13):5648-63.
• [18] Beta-carotene and apocarotenals promote retinoid signaling in BEAS-2B human bronchioepithelial cells. Arch Biochem Biophys. 2006 Nov 1;455(1):48-60.
• [19] Identification of biomarkers modulated by the rexinoid LGD1069 (bexarotene) in human breast cells using oligonucleotide arrays. Cancer Res. 2006 Dec 15;66(24):12009-18.
• [20] Gene-specific TCDD suppression of RARalpha- and RXR-mediated induction of tissue transglutaminase. Toxicol Sci. 2002 Jul;68(1):102-8. doi: 10.1093/toxsci/68.1.102.
• [21] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [22] New benzoic acid derivatives with retinoid activity: lack of direct correlation between biological activity and binding to cellular retinoic acid binding protein. Cancer Res. 1987 Jul 1;47(13):3523-7.
• [23] PRC2 loss amplifies Ras-driven transcription and confers sensitivity to BRD4-based therapies. Nature. 2014 Oct 9;514(7521):247-51.
• [24] 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.
• [25] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [26] 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.
• [27] Tissue transglutaminase serves as an inhibitor of apoptosis by cross-linking caspase 3 in thapsigargin-treated cells. Mol Cell Biol. 2006 Jan;26(2):569-79.
• [28] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [29] Identification of transcriptome signatures and biomarkers specific for potential developmental toxicants inhibiting human neural crest cell migration. Arch Toxicol. 2016 Jan;90(1):159-80.
• [30] Regulation of chromatin assembly and cell transformation by formaldehyde exposure in human cells. Environ Health Perspect. 2017 Sep 21;125(9):097019.
• [31] Molecular mechanisms of quercitrin-induced apoptosis in non-small cell lung cancer. Arch Med Res. 2014 Aug;45(6):445-54.
• [32] Neurite outgrowth inhibitory levels of organophosphates induce tissue transglutaminase activity in differentiating N2a cells: evidence for covalent adduct formation. Arch Toxicol. 2020 Nov;94(11):3861-3875. doi: 10.1007/s00204-020-02852-w. Epub 2020 Aug 4.
• [33] Overexpression of transglutaminase 2 accelerates the erythroid differentiation of human chronic myelogenous leukemia K562 cell line through PI3K/Akt signaling pathway. FEBS Lett. 2004 Nov 19;577(3):361-6. doi: 10.1016/j.febslet.2004.10.031.
• [34] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.