Details of Drug Off-Target (DOT)

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

• DOT Name: Granzyme B (GZMB)
• Synonyms: EC 3.4.21.79; C11; CTLA-1; Cathepsin G-like 1; CTSGL1; Cytotoxic T-lymphocyte proteinase 2; Lymphocyte protease; Fragmentin-2; Granzyme-2; Human lymphocyte protein; HLP; SECT; T-cell serine protease 1-3E
• Gene Name: GZMB
• UniProt ID: GRAB_HUMAN
• PDB ID: 1FQ3; 1IAU
• EC Number: 3.4.21.79
• Pfam ID: PF00089
• Sequence:
  MQPILLLLAFLLLPRADAGEIIGGHEAKPHSRPYMAYLMIWDQKSLKRCGGFLIRDDFVL
  TAAHCWGSSINVTLGAHNIKEQEPTQQFIPVKRPIPHPAYNPKNFSNDIMLLQLERKAKR
  TRAVQPLRLPSNKAQVKPGQTCSVAGWGQTAPLGKHSHTLQEVKMTVQEDRKCESDLRHY
  YDSTIELCVGDPEIKKTSFKGDSGGPLVCNKVAQGIVSYGRNNGMPPRACTKVSSFVHWI
  KKTMKRY
• 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 Asp. Once delivered into the target cell, acts by catalyzing cleavage of gasdermin-E (GSDME), releasing the pore-forming moiety of GSDME, thereby triggering pyroptosis and target cell death. Seems to be linked to an activation cascade of caspases (aspartate-specific cysteine proteases) responsible for apoptosis execution. Cleaves caspase-3, -9 and -10 (CASP3, CASP9 and CASP10, respectively) to give rise to active enzymes mediating apoptosis. Cleaves and activates CASP7 in response to bacterial infection, promoting plasma membrane repair.
• KEGG Pathway:
  Apoptosis (hsa04210)
  .tural killer cell mediated cytotoxicity (hsa04650)
  Type I diabetes mellitus (hsa04940)
  Transcriptio.l misregulation in cancer (hsa05202)
  Autoimmune thyroid disease (hsa05320)
  Allograft rejection (hsa05330)
  Graft-versus-host disease (hsa05332)
• Reactome Pathway:
  Pyroptosis (R-HSA-5620971)
  Activation, myristolyation of BID and translocation to mitochondria (R-HSA-75108)
  NOTCH2 intracellular domain regulates transcription (R-HSA-2197563)

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Pentoxifylline	DMU3DNC	Approved	Granzyme B (GZMB) increases the Cell death ADR of Pentoxifylline.	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Granzyme B (GZMB).	[1]
Marinol	DM70IK5	Approved	Marinol increases the expression of Granzyme B (GZMB).	[3]
Zoledronate	DMIXC7G	Approved	Zoledronate affects the expression of Granzyme B (GZMB).	[4]
Fulvestrant	DM0YZC6	Approved	Fulvestrant decreases the expression of Granzyme B (GZMB).	[5]
Bortezomib	DMNO38U	Approved	Bortezomib increases the expression of Granzyme B (GZMB).	[6]
Menthol	DMG2KW7	Approved	Menthol increases the expression of Granzyme B (GZMB).	[7]
phorbol 12-myristate 13-acetate	DMJWD62	Phase 2	phorbol 12-myristate 13-acetate increases the expression of Granzyme B (GZMB).	[9]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Granzyme B (GZMB).	[10]
Rapamycin Immunosuppressant Drug	DM678IB	Investigative	Rapamycin Immunosuppressant Drug decreases the expression of Granzyme B (GZMB).	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Carbamazepine	DMZOLBI	Approved	Carbamazepine increases the secretion of Granzyme B (GZMB).	[2]
Rifampicin	DM5DSFZ	Approved	Rifampicin increases the secretion of Granzyme B (GZMB).	[8]
Ethambutol	DMR87LC	Approved	Ethambutol increases the secretion of Granzyme B (GZMB).	[8]

References

• [1] All-trans retinoic acid negatively regulates cytotoxic activities of nature killer cell line 92. Biochem Biophys Res Commun. 2007 Jan 5;352(1):42-7. doi: 10.1016/j.bbrc.2006.10.132. Epub 2006 Nov 2.
• [2] Up-Regulation of T-Cell Activation MicroRNAs in Drug-Specific CD4(+) T-Cells from Hypersensitive Patients. Chem Res Toxicol. 2018 Jun 18;31(6):454-461. doi: 10.1021/acs.chemrestox.7b00330. Epub 2018 May 16.
• [3] Single-cell Transcriptome Mapping Identifies Common and Cell-type Specific Genes Affected by Acute Delta9-tetrahydrocannabinol in Humans. Sci Rep. 2020 Feb 26;10(1):3450. doi: 10.1038/s41598-020-59827-1.
• [4] Defective gammadelta T-cell function and granzyme B gene polymorphism in a cohort of newly diagnosed breast cancer patients. Exp Hematol. 2009 Jul;37(7):838-48. doi: 10.1016/j.exphem.2009.04.003. Epub 2009 May 14.
• [5] Antiestrogens induce transforming growth factor beta-mediated immunosuppression in breast cancer. Cancer Res. 2010 Feb 15;70(4):1314-22. doi: 10.1158/0008-5472.CAN-09-3292. Epub 2010 Feb 9.
• [6] 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.
• [7] Repurposing L-menthol for systems medicine and cancer therapeutics? L-menthol induces apoptosis through caspase 10 and by suppressing HSP90. OMICS. 2016 Jan;20(1):53-64.
• [8] Detection of Drug-Responsive T-Lymphocytes in a Case of Fatal Antituberculosis Drug-Related Liver Injury. Chem Res Toxicol. 2016 Nov 21;29(11):1793-1795. doi: 10.1021/acs.chemrestox.6b00393. Epub 2016 Nov 9.
• [9] Activation of p44/42 in human natural killer cells decreases cell-surface protein expression: Relationship to tributyltin-induced alterations of protein expression. Toxicol Mech Methods. 2010 Nov;20(9):544-55. doi: 10.3109/15376516.2010.518174. Epub 2010 Sep 30.
• [10] 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.
• [11] Rapamycin does not induce anergy but inhibits expansion and differentiation of alloreactive human T cells. Transplantation. 2006 Feb 15;81(3):445-54. doi: 10.1097/01.tp.0000194860.21533.b9.
• [12] ADReCS-Target: target profiles for aiding drug safety research and application. Nucleic Acids Res. 2018 Jan 4;46(D1):D911-D917. doi: 10.1093/nar/gkx899.