Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT85ZMQG)

• DOT Name: Cathepsin G (CTSG)
• Synonyms: CG; EC 3.4.21.20
• Gene Name: CTSG
• UniProt ID: CATG_HUMAN
• PDB ID: 1AU8; 1CGH; 1KYN; 1T32; 6VTM; 8D4S; 8D4V; 8D7I; 8D7K; 8G24; 8G25; 8G26
• EC Number: 3.4.21.20
• Pfam ID: PF00089
• Sequence:
  MQPLLLLLAFLLPTGAEAGEIIGGRESRPHSRPYMAYLQIQSPAGQSRCGGFLVREDFVL
  TAAHCWGSNINVTLGAHNIQRRENTQQHITARRAIRHPQYNQRTIQNDIMLLQLSRRVRR
  NRNVNPVALPRAQEGLRPGTLCTVAGWGRVSMRRGTDTLREVQLRVQRDRQCLRIFGSYD
  PRRQICVGDRRERKAAFKGDSGGPLLCNNVAHGIVSYGKSSGVPPEVFTRVSSFLPWIRT
  TMRSFKLLDQMETPL
• Function: Serine protease with trypsin- and chymotrypsin-like specificity. Also displays antibacterial activity against Gram-negative and Gram-positive bacteria independent of its protease activity. Prefers Phe and Tyr residues in the P1 position of substrates but also cleaves efficiently after Trp and Leu. Shows a preference for negatively charged amino acids in the P2' position and for aliphatic amino acids both upstream and downstream of the cleavage site. Required for recruitment and activation of platelets which is mediated by the F2RL3/PAR4 platelet receptor. Binds reversibly to and stimulates B cells and CD4(+) and CD8(+) T cells. Also binds reversibly to natural killer (NK) cells and enhances NK cell cytotoxicity through its protease activity. Cleaves complement C3. Cleaves vimentin. Cleaves thrombin receptor F2R/PAR1 and acts as either an agonist or an inhibitor, depending on the F2R cleavage site. Cleavage of F2R at '41-Arg-|-Ser-42' results in receptor activation while cleavage at '55-Phe-|-Trp-56' results in inhibition of receptor activation. Cleaves the synovial mucin-type protein PRG4/lubricin. Cleaves and activates IL36G which promotes expression of chemokines CXCL1 and CXLC8 in keratinocytes. Cleaves IL33 into mature forms which have greater activity than the unprocessed form. Cleaves coagulation factor F8 to produce a partially activated form. Also cleaves and activates coagulation factor F10. Cleaves leukocyte cell surface protein SPN/CD43 to releases its extracellular domain and trigger its intramembrane proteolysis by gamma-secretase, releasing the CD43 cytoplasmic tail chain (CD43-ct) which translocates to the nucleus. Cleaves CCL5/RANTES to produce RANTES(4-68) lacking the N-terminal three amino acids which exhibits reduced chemotactic and antiviral activities. During apoptosis, cleaves SMARCA2/BRM to produce a 160 kDa cleavage product which localizes to the cytosol. Cleaves myelin basic protein MBP in B cell lysosomes at '224-Phe-|-Lys-225' and '248-Phe-|-Ser-249', degrading the major immunogenic MBP epitope and preventing the activation of MBP-specific autoreactive T cells. Cleaves annexin ANXA1 and antimicrobial peptide CAMP to produce peptides which act on neutrophil N-formyl peptide receptors to enhance the release of CXCL2. Acts as a ligand for the N-formyl peptide receptor FPR1, enhancing phagocyte chemotaxis. Has antibacterial activity against the Gram-negative bacteria N.gonorrhoeae and P.aeruginosa. Likely to act against N.gonorrhoeae by interacting with N.gonorrhoeae penA/PBP2. Exhibits potent antimicrobial activity against the Gram-positive bacterium L.monocytogenes. Has antibacterial activity against the Gram-positive bacterium S.aureus and degrades S.aureus biofilms, allowing polymorphonuclear leukocytes to penetrate the biofilm and phagocytose bacteria. Has antibacterial activity against M.tuberculosis. Mediates CASP4 activation induced by the Td92 surface protein of the periodontal pathogen T.denticola, causing production and secretion of IL1A and leading to pyroptosis of gingival fibroblasts.
• Tissue Specificity: Expressed in neutrophils (at protein level) . Expressed in B cells .
• KEGG Pathway:
  Neuroactive ligand-receptor interaction (hsa04080)
  Lysosome (hsa04142)
  Neutrophil extracellular trap formation (hsa04613)
  Renin-angiotensin system (hsa04614)
  Amoebiasis (hsa05146)
  Systemic lupus erythematosus (hsa05322)
• Reactome Pathway:
  Activation of Matrix Metalloproteinases (R-HSA-1592389)
  Metabolism of Angiotensinogen to Angiotensins (R-HSA-2022377)
  Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs) (R-HSA-381426)
  Interleukin-1 processing (R-HSA-448706)
  Neutrophil degranulation (R-HSA-6798695)
  Antimicrobial peptides (R-HSA-6803157)
  Suppression of apoptosis (R-HSA-9635465)
  Purinergic signaling in leishmaniasis infection (R-HSA-9660826)
  Degradation of the extracellular matrix (R-HSA-1474228)

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
Doxorubicin	DMVP5YE	Approved	Cathepsin G (CTSG) affects the response to substance of Doxorubicin.	[10]

This DOT Affected the Biotransformations of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Aniline	DMLCAR9	Investigative	Cathepsin G (CTSG) increases the hydrolysis of Aniline.	[11]

7 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 Cathepsin G (CTSG).	[1]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Cathepsin G (CTSG).	[2]
Arsenic	DMTL2Y1	Approved	Arsenic affects the expression of Cathepsin G (CTSG).	[3]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Cathepsin G (CTSG).	[4]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Cathepsin G (CTSG).	[7]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of Cathepsin G (CTSG).	[8]
Y-40613	DM412IV	Investigative	Y-40613 decreases the activity of Cathepsin G (CTSG).	[9]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
phorbol 12-myristate 13-acetate	DMJWD62	Phase 2	phorbol 12-myristate 13-acetate increases the secretion of Cathepsin G (CTSG).	[5]
Fmet-leu-phe	DMQ391A	Investigative	Fmet-leu-phe increases the secretion of Cathepsin G (CTSG).	[5]

1 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 Cathepsin G (CTSG).	[6]

References

• [1] Systems analysis of transcriptome and proteome in retinoic acid/arsenic trioxide-induced cell differentiation/apoptosis of promyelocytic leukemia. Proc Natl Acad Sci U S A. 2005 May 24;102(21):7653-8.
• [2] 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.
• [3] Fetal-sex dependent genomic responses in the circulating lymphocytes of arsenic-exposed pregnant women in New Hampshire. Reprod Toxicol. 2017 Oct;73:184-195. doi: 10.1016/j.reprotox.2017.07.023. Epub 2017 Aug 6.
• [4] The contribution of methotrexate exposure and host factors on transcriptional variance in human liver. Toxicol Sci. 2007 Jun;97(2):582-94.
• [5] The anti-inflammatory effect of 2-(4-hydroxy-3-prop-2-enyl-phenyl)-4-prop-2-enyl-phenol by targeting Lyn kinase in human neutrophils. Chem Biol Interact. 2015 Jul 5;236:90-101. doi: 10.1016/j.cbi.2015.05.004. Epub 2015 May 14.
• [6] 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.
• [7] Environmental pollutant induced cellular injury is reflected in exosomes from placental explants. Placenta. 2020 Jan 1;89:42-49. doi: 10.1016/j.placenta.2019.10.008. Epub 2019 Oct 17.
• [8] Sulforaphane-induced apoptosis in human leukemia HL-60 cells through extrinsic and intrinsic signal pathways and altering associated genes expression assayed by cDNA microarray. Environ Toxicol. 2017 Jan;32(1):311-328.
• [9] Therapeutic potential of a specific chymase inhibitor in atopic dermatitis. Jpn J Pharmacol. 2002 Nov;90(3):214-7.
• [10] Monitoring the gene expression profiles of doxorubicin-resistant acute myelocytic leukemia cells by DNA microarray analysis. Life Sci. 2006 Jun 6;79(2):193-202. doi: 10.1016/j.lfs.2005.12.054. Epub 2006 Feb 3.
• [11] Similarities between human and rat leukocyte elastase and cathepsin G. Eur J Biochem. 1984 Oct 1;144(1):1-9. doi: 10.1111/j.1432-1033.1984.tb08423.x.