Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTEC5CWT)

• DOT Name: Granzyme M (GZMM)
• Synonyms: EC 3.4.21.-; Met-1 serine protease; Hu-Met-1; Met-ase; Natural killer cell granular protease
• Gene Name: GZMM
• Related Disease:
  B-cell neoplasm
  Adult T-cell leukemia/lymphoma
  Advanced cancer
  Breast cancer
  Breast carcinoma
  Carcinoma
  Central diabetes insipidus
  Cytomegalovirus infection
  Glioblastoma multiforme
  Head-neck squamous cell carcinoma
  Immunodeficiency
  Inflammatory bowel disease
  Morton neuroma
  Neoplasm
  Prostate cancer
  Prostate carcinoma
  Rheumatoid arthritis
  T-cell leukaemia
  T-cell lymphoma
  Ulcerative colitis
  Sickle-cell anaemia
  Systemic primary carnitine deficiency disease
• UniProt ID: GRAM_HUMAN
• PDB ID: 2ZGC; 2ZGH; 2ZGJ; 2ZKS
• EC Number: 3.4.21.-
• Pfam ID: PF00089
• Sequence:
  MEACVSSLLVLALGALSVGSSFGTQIIGGREVIPHSRPYMASLQRNGSHLCGGVLVHPKW
  VLTAAHCLAQRMAQLRLVLGLHTLDSPGLTFHIKAAIQHPRYKPVPALENDLALLQLDGK
  VKPSRTIRPLALPSKRQVVAAGTRCSMAGWGLTHQGGRLSRVLRELDLQVLDTRMCNNSR
  FWNGSLSPSMVCLAADSKDQAPCKGDSGGPLVCGKGRVLARVLSFSSRVCTDIFKPPVAT
  AVAPYVSWIRKVTGRSA
• Function: Cleaves peptide substrates after methionine, leucine, and norleucine. Physiological substrates include EZR, alpha-tubulins and the apoptosis inhibitor BIRC5/Survivin. Promotes caspase activation and subsequent apoptosis of target cells.
• Tissue Specificity: Highly and constitutively expressed in activated natural killer (NK) cells.
• Reactome Pathway: Alternative complement activation (R-HSA-173736)

Molecular Interaction Atlas (MIA) of This DOT

22 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
B-cell neoplasm	DISVY326	Definitive	Genetic Variation	[1]
Adult T-cell leukemia/lymphoma	DIS882XU	Strong	Genetic Variation	[2]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[3]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[4]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[4]
Carcinoma	DISH9F1N	Strong	Biomarker	[5]
Central diabetes insipidus	DISJ4P9O	Strong	Biomarker	[6]
Cytomegalovirus infection	DISCEMGC	Strong	Altered Expression	[7]
Glioblastoma multiforme	DISK8246	Strong	Biomarker	[8]
Head-neck squamous cell carcinoma	DISF7P24	Strong	Biomarker	[9]
Immunodeficiency	DIS093I0	Strong	Biomarker	[10]
Inflammatory bowel disease	DISGN23E	Strong	Altered Expression	[11]
Morton neuroma	DISE0HPX	Strong	Biomarker	[12]
Neoplasm	DISZKGEW	Strong	Biomarker	[13]
Prostate cancer	DISF190Y	Strong	Biomarker	[13]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[13]
Rheumatoid arthritis	DISTSB4J	Strong	Biomarker	[14]
T-cell leukaemia	DISJ6YIF	Strong	Biomarker	[15]
T-cell lymphoma	DISSXRTQ	Strong	Altered Expression	[16]
Ulcerative colitis	DIS8K27O	Strong	Biomarker	[11]
Sickle-cell anaemia	DIS5YNZB	Limited	Biomarker	[17]
Systemic primary carnitine deficiency disease	DIS9OPZ4	Limited	Biomarker	[17]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Granzyme M (GZMM).	[18]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Granzyme M (GZMM).	[19]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Granzyme M (GZMM).	[20]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Granzyme M (GZMM).	[21]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Granzyme M (GZMM).	[22]

References

• [1] Specific recognition of linear polyubiquitin by A20 zinc finger 7 is involved in NF-B regulation.EMBO J. 2012 Oct 3;31(19):3856-70. doi: 10.1038/emboj.2012.241. Epub 2012 Aug 28.
• [2] Combination of 9-aminoacridine with Campath-1H provides effective therapy for a murine model of adult T-cell leukemia.Retrovirology. 2014 Jun 2;11:43. doi: 10.1186/1742-4690-11-43.
• [3] The Met1-Linked Ubiquitin Machinery: Emerging Themes of (De)regulation.Mol Cell. 2017 Oct 19;68(2):265-280. doi: 10.1016/j.molcel.2017.09.001.
• [4] DACH1 suppresses breast cancer as a negative regulator of CD44.Sci Rep. 2017 Jun 28;7(1):4361. doi: 10.1038/s41598-017-04709-2.
• [5] An antisense oligodeoxynucleotide to p21(Waf1/Cip1) causes apoptosis in human breast cancer cells.Mol Cancer Ther. 2003 Aug;2(8):773-82.
• [6] Effects of defined gut microbial ecosystem components on virulence determinants of Clostridioides difficile.Sci Rep. 2019 Jan 29;9(1):885. doi: 10.1038/s41598-018-37547-x.
• [7] Granzyme M targets host cell hnRNP K that is essential for human cytomegalovirus replication.Cell Death Differ. 2013 Mar;20(3):419-29. doi: 10.1038/cdd.2012.132. Epub 2012 Oct 26.
• [8] Practical Bioinformatic DNA-Sequencing Pipeline for Detecting Oncogene Amplification and EGFRvIII Mutational Status in Clinical Glioblastoma Samples.J Mol Diagn. 2019 May;21(3):514-524. doi: 10.1016/j.jmoldx.2019.02.001. Epub 2019 Apr 15.
• [9] Down-regulation of S100A2 in lymph node metastases of head and neck cancer.Head Neck. 2007 Mar;29(3):236-43. doi: 10.1002/hed.20511.
• [10] Effective therapy for a murine model of adult T-cell leukemia with the humanized anti-CD52 monoclonal antibody, Campath-1H.Cancer Res. 2003 Oct 1;63(19):6453-7.
• [11] Granzyme M has a critical role in providing innate immune protection in ulcerative colitis.Cell Death Dis. 2016 Jul 21;7(7):e2302. doi: 10.1038/cddis.2016.215.
• [12] Radiographic Analysis of Feet With and Without Morton's Neuroma.Foot Ankle Int. 2017 Mar;38(3):310-317. doi: 10.1177/1071100716674998. Epub 2016 Nov 13.
• [13] Germline genetic variants in men with prostate cancer and one or more additional cancers.Cancer. 2017 Oct 15;123(20):3925-3932. doi: 10.1002/cncr.30817. Epub 2017 Jun 28.
• [14] Increased intra-articular granzyme M may trigger local IFN-1/IL-29 response in rheumatoid arthritis.Clin Exp Rheumatol. 2020 Mar-Apr;38(2):220-226. doi: 10.55563/clinexprheumatol/ffb107. Epub 2019 Jun 6.
• [15] Markedly additive antitumor activity with the combination of a selective survivin suppressant YM155 and alemtuzumab in adult T-cell leukemia.Blood. 2013 Mar 14;121(11):2029-37. doi: 10.1182/blood-2012-05-427773. Epub 2013 Jan 15.
• [16] The serine protease granzyme M is preferentially expressed in NK-cell, gamma delta T-cell, and intestinal T-cell lymphomas: evidence of origin from lymphocytes involved in innate immunity.Blood. 2003 May 1;101(9):3590-3. doi: 10.1182/blood-2002-09-2908. Epub 2002 Dec 27.
• [17] Homozygous DMRT2 variant associates with severe rib malformations in a newborn.Am J Med Genet A. 2018 May;176(5):1216-1221. doi: 10.1002/ajmg.a.38668.
• [18] 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.
• [19] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [20] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [21] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [22] 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.