Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTG3259L)

• DOT Name: Granzyme H (GZMH)
• Synonyms: EC 3.4.21.-; CCP-X; Cathepsin G-like 2; CTSGL2; Cytotoxic T-lymphocyte proteinase; Cytotoxic serine protease C; CSP-C
• Gene Name: GZMH
• Related Disease:
  Congenital generalized lipodystrophy
  Hepatitis C virus infection
  Lymphoproliferative syndrome
  Familial partial lipodystrophy
  Hereditary lipodystrophy
  Osteopoikilosis
  Extranodal NK/T-cell Lymphoma
  Cognitive impairment
• UniProt ID: GRAH_HUMAN
• PDB ID: 3TJU; 3TJV; 3TK9; 4GAW
• EC Number: 3.4.21.-
• Pfam ID: PF00089
• Sequence:
  MQPFLLLLAFLLTPGAGTEEIIGGHEAKPHSRPYMAFVQFLQEKSRKRCGGILVRKDFVL
  TAAHCQGSSINVTLGAHNIKEQERTQQFIPVKRPIPHPAYNPKNFSNDIMLLQLERKAKW
  TTAVRPLRLPSSKAQVKPGQLCSVAGWGYVSMSTLATTLQEVLLTVQKDCQCERLFHGNY
  SRATEICVGDPKKTQTGFKGDSGGPLVCKDVAQGILSYGNKKGTPPGVYIKVSHFLPWIK
  RTMKRL
• Function: Cytotoxic chymotrypsin-like serine protease with preference for bulky and aromatic residues at the P1 position and acidic residues at the P3' and P4' sites. Probably necessary for target cell lysis in cell-mediated immune responses. Participates in the antiviral response via direct cleavage of several proteins essential for viral replication.
• Tissue Specificity: Constitutively expressed in NK cells.
• Reactome Pathway:
  Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs) (R-HSA-381426)
  Metabolism of Angiotensinogen to Angiotensins (R-HSA-2022377)

Molecular Interaction Atlas (MIA) of This DOT

8 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Congenital generalized lipodystrophy	DIS4XF8N	Strong	Genetic Variation	[1]
Hepatitis C virus infection	DISQ0M8R	Strong	Altered Expression	[2]
Lymphoproliferative syndrome	DISMVL8O	Strong	Genetic Variation	[3]
Familial partial lipodystrophy	DISFVL9J	moderate	Biomarker	[4]
Hereditary lipodystrophy	DIS1BE1A	moderate	Biomarker	[4]
Osteopoikilosis	DISXDBD8	moderate	Biomarker	[4]
Extranodal NK/T-cell Lymphoma	DIS72GCL	Disputed	Biomarker	[5]
Cognitive impairment	DISH2ERD	Limited	Biomarker	[1]

2 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 H (GZMH).	[6]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Granzyme H (GZMH).	[7]

References

• [1] Seipin deletion in mice enhances phosphorylation and aggregation of tau protein through reduced neuronal PPAR and insulin resistance.Neurobiol Dis. 2019 Jul;127:350-361. doi: 10.1016/j.nbd.2019.03.023. Epub 2019 Mar 22.
• [2] Cleavage of La protein by granzyme H induces cytoplasmic translocation and interferes with La-mediated HCV-IRES translational activity.Cell Death Differ. 2009 Feb;16(2):340-8. doi: 10.1038/cdd.2008.165. Epub 2008 Nov 28.
• [3] Characterization of a novel, human cytotoxic lymphocyte-specific serine protease cDNA clone (CSP-C).Tissue Antigens. 1990 May;35(5):220-8. doi: 10.1111/j.1399-0039.1990.tb01787.x.
• [4] Bone imaging findings in genetic and acquired lipodystrophic syndromes: an imaging study of 24 cases.Skeletal Radiol. 2016 Nov;45(11):1495-506. doi: 10.1007/s00256-016-2457-9. Epub 2016 Sep 8.
• [5] Molecular underpinning of extranodal NK/T-cell lymphoma.Best Pract Res Clin Haematol. 2013 Mar;26(1):57-74. doi: 10.1016/j.beha.2013.04.006. Epub 2013 May 23.
• [6] 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.
• [7] 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.