Details of Drug Off-Target (DOT)

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

• DOT Name: Neutrophil elastase (ELANE)
• Synonyms: EC 3.4.21.37; Bone marrow serine protease; Elastase-2; Human leukocyte elastase; HLE; Medullasin; PMN elastase
• Gene Name: ELANE
• Related Disease:
  Neutropenia
  Cyclic hematopoiesis
  Autosomal dominant severe congenital neutropenia
• UniProt ID: ELNE_HUMAN
• PDB ID: 1B0F; 1H1B; 1HNE; 1PPF; 1PPG; 2RG3; 2Z7F; 3Q76; 3Q77; 4NZL; 4WVP; 5A09; 5A0A; 5A0B; 5A0C; 5A8X; 5A8Y; 5A8Z; 5ABW; 6E69; 6F5M; 6SMA; 7CBK; 7WHU; 8D4Q; 8D4U; 8D7I; 8D7K; 8G24; 8G25; 8G26
• EC Number: 3.4.21.37
• Pfam ID: PF00089
• Sequence:
  MTLGRRLACLFLACVLPALLLGGTALASEIVGGRRARPHAWPFMVSLQLRGGHFCGATLI
  APNFVMSAAHCVANVNVRAVRVVLGAHNLSRREPTRQVFAVQRIFENGYDPVNLLNDIVI
  LQLNGSATINANVQVAQLPAQGRRLGNGVQCLAMGWGLLGRNRGIASVLQELNVTVVTSL
  CRRSNVCTLVRGRQAGVCFGDSGSPLVCNGLIHGIASFVRGGCASGLYPDAFAPVAQFVN
  WIDSIIQRSEDNPCPHPRDPDPASRTH
• Function: Serine protease that modifies the functions of natural killer cells, monocytes and granulocytes. Inhibits C5a-dependent neutrophil enzyme release and chemotaxis. Promotes cleavage of GSDMB, thereby inhibiting pyroptosis. Capable of killing E.coli but not S.aureus in vitro; digests outer membrane protein A (ompA) in E.coli and K.pneumoniae.
• Tissue Specificity: Bone marrow cells. Neutrophil .
• KEGG Pathway:
  Neutrophil extracellular trap formation (hsa04613)
  Transcriptio.l misregulation in cancer (hsa05202)
  Systemic lupus erythematosus (hsa05322)
• Reactome Pathway:
  Degradation of the extracellular matrix (R-HSA-1474228)
  Activation of Matrix Metalloproteinases (R-HSA-1592389)
  Pyroptosis (R-HSA-5620971)
  Neutrophil degranulation (R-HSA-6798695)
  Antimicrobial peptides (R-HSA-6803157)
  Regulation of Complement cascade (R-HSA-977606)
  Collagen degradation (R-HSA-1442490)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Neutropenia	DISGCAMX	Definitive	Autosomal dominant	[1]
Cyclic hematopoiesis	DISQQOM4	Strong	Autosomal dominant	[2]
Autosomal dominant severe congenital neutropenia	DISZC7BV	Supportive	Autosomal dominant	[3]

This DOT Affected the Biotransformations of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Aniline	DMLCAR9	Investigative	Neutrophil elastase (ELANE) increases the hydrolysis of Aniline.	[12]

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 Neutrophil elastase (ELANE).	[4]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Neutrophil elastase (ELANE).	[8]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Neutrophil elastase (ELANE).	[5]
Glyceryl trinitrate	DMF72W3	Phase 4	Glyceryl trinitrate increases the expression of Neutrophil elastase (ELANE).	[6]
Paraquat	DMR8O3X	Investigative	Paraquat decreases the expression of Neutrophil elastase (ELANE).	[9]
KOJIC ACID	DMP84CS	Investigative	KOJIC ACID decreases the expression of Neutrophil elastase (ELANE).	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Lipoteichoic acid	DMEMRW0	Phase 1/2	Lipoteichoic acid increases the secretion of Neutrophil elastase (ELANE).	[7]
Fmet-leu-phe	DMQ391A	Investigative	Fmet-leu-phe increases the secretion of Neutrophil elastase (ELANE).	[11]

References

• [1] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [2] [Evaluation of driving-ability in handicapped]. Beitr Orthop Traumatol. 1975 Feb;22(2):134-5.
• [3] Clinical Practice Guidelines for Rare Diseases: The Orphanet Database. PLoS One. 2017 Jan 18;12(1):e0170365. doi: 10.1371/journal.pone.0170365. eCollection 2017.
• [4] 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.
• [5] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [6] Cardiopulmonary bypass exacerbates oxidative stress but does not increase proinflammatory cytokine release in patients with diabetes compared with patients without diabetes: regulatory effects of exogenous nitric oxide. J Thorac Cardiovasc Surg. 2000 Jul;120(1):1-11. doi: 10.1067/mtc.2000.106835.
• [7] Thalidomide inhibits granulocyte responses in healthy humans after ex vivo stimulation with bacterial antigens. Antimicrob Agents Chemother. 2001 May;45(5):1547-9. doi: 10.1128/AAC.45.5.1547-1549.2001.
• [8] 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.
• [9] CD34+ derived macrophage and dendritic cells display differential responses to paraquat. Toxicol In Vitro. 2021 Sep;75:105198. doi: 10.1016/j.tiv.2021.105198. Epub 2021 Jun 9.
• [10] Toxicogenomics of kojic acid on gene expression profiling of a375 human malignant melanoma cells. Biol Pharm Bull. 2006 Apr;29(4):655-69.
• [11] 2-(2-Fluorobenzamido)benzoate ethyl ester (EFB-1) inhibits superoxide production by human neutrophils and attenuates hemorrhagic shock-induced organ dysfunction in rats. Free Radic Biol Med. 2011 Jun 15;50(12):1737-48. doi: 10.1016/j.freeradbiomed.2011.03.026. Epub 2011 Mar 30.
• [12] 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.