Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT43R33L)

• DOT Name: Granzyme A (GZMA)
• Synonyms: EC 3.4.21.78; CTL tryptase; Cytotoxic T-lymphocyte proteinase 1; Fragmentin-1; Granzyme-1; Hanukkah factor; H factor; HF
• Gene Name: GZMA
• Related Disease:
  Pneumonia
  Pulmonary disease
  Acute lymphocytic leukaemia
  Acute myelogenous leukaemia
  Acute myocardial infarction
  Adult respiratory distress syndrome
  Advanced cancer
  Chikungunya virus infection
  Chilblain lupus
  Chilblain lupus 1
  Childhood acute lymphoblastic leukemia
  Eclampsia
  Endometrial carcinoma
  Gastric cancer
  Herpes simplex infection
  Influenza
  Lung cancer
  Lung carcinoma
  Mucocutaneous leishmaniasis
  Multiple sclerosis
  Non-small-cell lung cancer
  Osteoarthritis
  Psoriasis
  Psoriatic arthritis
  Rheumatoid arthritis
  Sjogren syndrome
  Stomach cancer
  T-cell lymphoma
  Tuberculosis
  Ulcerative colitis
  Bladder cancer
  Graft-versus-host disease
  Scleroderma
  Systemic sclerosis
  Urinary bladder cancer
  Urinary bladder neoplasm
  Arthritis
  Chronic obstructive pulmonary disease
  Neoplasm
  Pulmonary tuberculosis
• UniProt ID: GRAA_HUMAN
• PDB ID: 1OP8; 1ORF
• EC Number: 3.4.21.78
• Pfam ID: PF00089
• Sequence:
  MRNSYRFLASSLSVVVSLLLIPEDVCEKIIGGNEVTPHSRPYMVLLSLDRKTICAGALIA
  KDWVLTAAHCNLNKRSQVILGAHSITREEPTKQIMLVKKEFPYPCYDPATREGDLKLLQL
  MEKAKINKYVTILHLPKKGDDVKPGTMCQVAGWGRTHNSASWSDTLREVNITIIDRKVCN
  DRNHYNFNPVIGMNMVCAGSLRGGRDSCNGDSGSPLLCEGVFRGVTSFGLENKCGDPRGP
  GVYILLSKKHLNWIIMTIKGAV
• Function: Abundant protease in the cytosolic granules of cytotoxic T-cells and NK-cells which activates caspase-independent pyroptosis when delivered into the target cell through the immunological synapse. It cleaves after Lys or Arg. Once delivered into the target cell, acts by catalyzing cleavage of gasdermin-B (GSDMB), releasing the pore-forming moiety of GSDMB, thereby triggering pyroptosis and target cell death. Cleaves APEX1 after 'Lys-31' and destroys its oxidative repair activity. Cleaves the nucleosome assembly protein SET after 'Lys-189', which disrupts its nucleosome assembly activity and allows the SET complex to translocate into the nucleus to nick and degrade the DNA.
• KEGG Pathway: Neuroactive ligand-receptor interaction (hsa04080)

Molecular Interaction Atlas (MIA) of This DOT

40 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Pneumonia	DIS8EF3M	Definitive	Altered Expression	[1]
Pulmonary disease	DIS6060I	Definitive	Altered Expression	[1]
Acute lymphocytic leukaemia	DISPX75S	Strong	Biomarker	[2]
Acute myelogenous leukaemia	DISCSPTN	Strong	Altered Expression	[3]
Acute myocardial infarction	DISE3HTG	Strong	Altered Expression	[4]
Adult respiratory distress syndrome	DISIJV47	Strong	Altered Expression	[5]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[6]
Chikungunya virus infection	DISDXEHY	Strong	Biomarker	[7]
Chilblain lupus	DIS5792K	Strong	Biomarker	[8]
Chilblain lupus 1	DISEBS1O	Strong	Biomarker	[8]
Childhood acute lymphoblastic leukemia	DISJ5D6U	Strong	Biomarker	[2]
Eclampsia	DISWPO8U	Strong	Biomarker	[9]
Endometrial carcinoma	DISXR5CY	Strong	Altered Expression	[10]
Gastric cancer	DISXGOUK	Strong	Genetic Variation	[11]
Herpes simplex infection	DISL1SAV	Strong	Biomarker	[12]
Influenza	DIS3PNU3	Strong	Altered Expression	[13]
Lung cancer	DISCM4YA	Strong	Altered Expression	[14]
Lung carcinoma	DISTR26C	Strong	Altered Expression	[14]
Mucocutaneous leishmaniasis	DISQEME2	Strong	Altered Expression	[15]
Multiple sclerosis	DISB2WZI	Strong	Biomarker	[16]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Altered Expression	[17]
Osteoarthritis	DIS05URM	Strong	Altered Expression	[18]
Psoriasis	DIS59VMN	Strong	Biomarker	[19]
Psoriatic arthritis	DISLWTG2	Strong	Biomarker	[20]
Rheumatoid arthritis	DISTSB4J	Strong	Biomarker	[21]
Sjogren syndrome	DISUBX7H	Strong	Altered Expression	[22]
Stomach cancer	DISKIJSX	Strong	Genetic Variation	[11]
T-cell lymphoma	DISSXRTQ	Strong	Biomarker	[23]
Tuberculosis	DIS2YIMD	Strong	Altered Expression	[1]
Ulcerative colitis	DIS8K27O	Strong	Biomarker	[24]
Bladder cancer	DISUHNM0	moderate	Altered Expression	[25]
Graft-versus-host disease	DIS0QADF	moderate	Biomarker	[26]
Scleroderma	DISVQ342	moderate	Altered Expression	[27]
Systemic sclerosis	DISF44L6	moderate	Altered Expression	[27]
Urinary bladder cancer	DISDV4T7	moderate	Altered Expression	[25]
Urinary bladder neoplasm	DIS7HACE	moderate	Altered Expression	[25]
Arthritis	DIST1YEL	Limited	Biomarker	[28]
Chronic obstructive pulmonary disease	DISQCIRF	Limited	Altered Expression	[29]
Neoplasm	DISZKGEW	Limited	Altered Expression	[30]
Pulmonary tuberculosis	DIS6FLUM	Limited	Biomarker	[31]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Granzyme A (GZMA).	[32]
Bortezomib	DMNO38U	Approved	Bortezomib decreases the expression of Granzyme A (GZMA).	[33]
Aspirin	DM672AH	Approved	Aspirin decreases the expression of Granzyme A (GZMA).	[34]
Capsaicin	DMGMF6V	Approved	Capsaicin increases the expression of Granzyme A (GZMA).	[35]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Granzyme A (GZMA).	[36]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Granzyme A (GZMA).	[38]

2 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 increases the methylation of Granzyme A (GZMA).	[37]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Granzyme A (GZMA).	[39]

References

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• [3] Serum proteomic spectral characteristics of acute myeloid leukemia and their clinical significance.Genet Mol Res. 2017 Apr 13;16(2). doi: 10.4238/gmr16029172.
• [4] Biomarkers identification for acute myocardial infarction detection via weighted gene co-expression network analysis.Medicine (Baltimore). 2017 Nov;96(47):e8375. doi: 10.1097/MD.0000000000008375.
• [5] Upregulation of two death pathways of perforin/granzyme and FasL/Fas in septic acute respiratory distress syndrome.Am J Respir Crit Care Med. 2000 Jan;161(1):237-43. doi: 10.1164/ajrccm.161.1.9810007.
• [6] Pathways- and epigenetic-based assessment of relative immune infiltration in various types of solid tumors.Adv Cancer Res. 2019;142:107-143. doi: 10.1016/bs.acr.2019.01.003. Epub 2019 Mar 6.
• [7] RNA-Seq analysis of chikungunya virus infection and identification of granzyme A as a major promoter of arthritic inflammation.PLoS Pathog. 2017 Feb 16;13(2):e1006155. doi: 10.1371/journal.ppat.1006155. eCollection 2017 Feb.
• [8] A mutation in TREX1 that impairs susceptibility to granzyme A-mediated cell death underlies familial chilblain lupus.J Mol Med (Berl). 2007 May;85(5):531-7. doi: 10.1007/s00109-007-0199-9. Epub 2007 Apr 18.
• [9] Identification of potential crucial genes associated with early-onset pre-eclampsia via a microarray analysis.J Obstet Gynaecol Res. 2017 May;43(5):812-819. doi: 10.1111/jog.13275.
• [10] Functional significance of cytochrome P450 1B1 in endometrial carcinogenesis.Cancer Res. 2009 Sep 1;69(17):7038-45. doi: 10.1158/0008-5472.CAN-09-1691. Epub 2009 Aug 18.
• [11] Identification of discrepancy between CTLA4 expression and CTLA4 activation in gastric cancer.Immunopharmacol Immunotoxicol. 2019 Jun;41(3):386-393. doi: 10.1080/08923973.2018.1533968. Epub 2018 Nov 13.
• [12] Granzyme A, a noncytolytic component of CD8(+) cell granules, restricts the spread of herpes simplex virus in the peripheral nervous systems of experimentally infected mice.J Virol. 2000 Jan;74(2):1029-32. doi: 10.1128/jvi.74.2.1029-1032.2000.
• [13] Examination of influenza specific T cell responses after influenza virus challenge in individuals vaccinated with MVA-NP+M1 vaccine.PLoS One. 2013 May 3;8(5):e62778. doi: 10.1371/journal.pone.0062778. Print 2013.
• [14] Adoptive immunotherapy of lung cancer with immobilized anti-TCRgammadelta antibody-expanded human gammadelta T-cells in peripheral blood.Cancer Biol Ther. 2009 Aug;8(16):1540-9. doi: 10.4161/cbt.8.16.8950. Epub 2009 Aug 8.
• [15] In Situ Cellular Response Underlying Successful Treatment of Mucosal Leishmaniasis with a Combination of Pentavalent Antimonial and Pentoxifylline.Am J Trop Med Hyg. 2019 Aug;101(2):392-401. doi: 10.4269/ajtmh.19-0139.
• [16] Cerebrospinal fluid biomarkers link toxic astrogliosis and microglial activation to multiple sclerosis severity.Mult Scler Relat Disord. 2019 Feb;28:34-43. doi: 10.1016/j.msard.2018.11.032. Epub 2018 Dec 5.
• [17] Tumor-infiltrating regulatory T cells inhibit endogenous cytotoxic T cell responses to lung adenocarcinoma.J Immunol. 2013 Aug 15;191(4):2009-17. doi: 10.4049/jimmunol.1301317. Epub 2013 Jul 12.
• [18] CD56(+)/CD16(-) Natural Killer cells expressing the inflammatory protease granzyme A are enriched in synovial fluid from patients with osteoarthritis.Osteoarthritis Cartilage. 2017 Oct;25(10):1708-1718. doi: 10.1016/j.joca.2017.06.007. Epub 2017 Jun 29.
• [19] Granzyme A potentiates chemokine production in IL-17-stimulated keratinocytes.Exp Dermatol. 2017 Sep;26(9):824-827. doi: 10.1111/exd.13284. Epub 2017 Apr 10.
• [20] Polyfunctional, Proinflammatory, Tissue-Resident Memory Phenotype and Function of Synovial Interleukin-17A+CD8+ T Cells in Psoriatic Arthritis.Arthritis Rheumatol. 2020 Mar;72(3):435-447. doi: 10.1002/art.41156. Epub 2020 Feb 4.
• [21] Granzyme A Contributes to Inflammatory Arthritis in Mice Through Stimulation of Osteoclastogenesis.Arthritis Rheumatol. 2017 Feb;69(2):320-334. doi: 10.1002/art.39857.
• [22] Lesional CD4+ IFN-+ cytotoxic T lymphocytes in IgG4-related dacryoadenitis and sialoadenitis.Ann Rheum Dis. 2017 Feb;76(2):377-385. doi: 10.1136/annrheumdis-2016-209139. Epub 2016 Jun 29.
• [23] NK/T-cell lymphoma associated with Epstein-Barr virus in a patient infected with human immunodeficiency virus: an autopsy case.Int J Hematol. 2004 Jun;79(5):480-3. doi: 10.1532/ijh97.a10316.
• [24] Association Between Response to Etrolizumab and Expression of Integrin E and Granzyme A in Colon Biopsies of Patients With Ulcerative Colitis.Gastroenterology. 2016 Feb;150(2):477-87.e9. doi: 10.1053/j.gastro.2015.10.041. Epub 2015 Oct 30.
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• [26] Granzyme A Is Required for Regulatory T-Cell Mediated Prevention of Gastrointestinal Graft-versus-Host Disease.PLoS One. 2015 Apr 30;10(4):e0124927. doi: 10.1371/journal.pone.0124927. eCollection 2015.
• [27] Gammadelta receptor bearing T cells in scleroderma: enhanced interaction with vascular endothelial cells in vitro.Clin Immunol. 1999 May;91(2):188-95. doi: 10.1006/clim.1999.4694.
• [28] How to straighten out that which bends up.Sci Transl Med. 2017 Mar 29;9(383):eaan0773. doi: 10.1126/scitranslmed.aan0773.
• [29] Increased granzyme A expression in type II pneumocytes of patients with severe chronic obstructive pulmonary disease.Am J Respir Crit Care Med. 2007 Mar 1;175(5):464-72. doi: 10.1164/rccm.200602-169OC. Epub 2006 Nov 30.
• [30] RNA-seq for identification of therapeutically targetable determinants of immune activation in human glioblastoma.J Neurooncol. 2019 Jan;141(1):95-102. doi: 10.1007/s11060-018-03010-0. Epub 2018 Oct 23.
• [31] Regulatory role of 1, 25-dihydroxyvitamin D3 and vitamin D receptor gene variants on intracellular granzyme A expression in pulmonary tuberculosis.Exp Mol Pathol. 2009 Feb;86(1):69-73. doi: 10.1016/j.yexmp.2008.10.002. Epub 2008 Oct 30.
• [32] The contribution of methotrexate exposure and host factors on transcriptional variance in human liver. Toxicol Sci. 2007 Jun;97(2):582-94.
• [33] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [34] Lunasin, a novel seed peptide, sensitizes human breast cancer MDA-MB-231 cells to aspirin-arrested cell cycle and induced apoptosis. Chem Biol Interact. 2010 Jul 30;186(2):127-34. doi: 10.1016/j.cbi.2010.04.027. Epub 2010 May 21.
• [35] Capsaicin promotes a more aggressive gene expression phenotype and invasiveness in null-TRPV1 urothelial cancer cells. Carcinogenesis. 2011 May;32(5):686-94. doi: 10.1093/carcin/bgr025. Epub 2011 Feb 10.
• [36] Regulation of gene expression and inhibition of experimental prostate cancer bone metastasis by dietary genistein. Neoplasia. 2004 Jul-Aug;6(4):354-63. doi: 10.1593/neo.03478.
• [37] 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.
• [38] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.
• [39] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.