Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTFGP3UR)

• DOT Name: Kallikrein-1 (KLK1)
• Synonyms: EC 3.4.21.35; Kidney/pancreas/salivary gland kallikrein; Tissue kallikrein
• Gene Name: KLK1
• Related Disease: Pulmonary arterial hypertension
• UniProt ID: KLK1_HUMAN
• PDB ID: 1SPJ
• EC Number: 3.4.21.35
• Pfam ID: PF00089
• Sequence:
  MWFLVLCLALSLGGTGAAPPIQSRIVGGWECEQHSQPWQAALYHFSTFQCGGILVHRQWV
  LTAAHCISDNYQLWLGRHNLFDDENTAQFVHVSESFPHPGFNMSLLENHTRQADEDYSHD
  LMLLRLTEPADTITDAVKVVELPTEEPEVGSTCLASGWGSIEPENFSFPDDLQCVDLKIL
  PNDECKKAHVQKVTDFMLCVGHLEGGKDTCVGDSGGPLMCDGVLQGVTSWGYVPCGTPNK
  PSVAVRVLSYVKWIEDTIAENS
• Function: Glandular kallikreins cleave Met-Lys and Arg-Ser bonds in kininogen to release Lys-bradykinin.; (Microbial infection) Cleaves Neisseria meningitidis NHBA in saliva; Neisseria is an obligate commensal of the nasopharyngeal mucosa.
• Tissue Specificity: Isoform 2 is expressed in pancreas, salivary glands, kidney, colon, prostate gland, testis, spleen and the colon adenocarcinoma cell line T84.
• KEGG Pathway:
  Renin-angiotensin system (hsa04614)
  Endocrine and other factor-regulated calcium reabsorption (hsa04961)
• Reactome Pathway: Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs) (R-HSA-381426)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Pulmonary arterial hypertension	DISP8ZX5	Limited	Autosomal dominant	[1]

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Cisplatin	DMRHGI9	Approved	Kallikrein-1 (KLK1) affects the response to substance of Cisplatin.	[6]
Dobutamine	DMD1B8Z	Approved	Kallikrein-1 (KLK1) affects the response to substance of Dobutamine.	[7]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Hydrocortisone	DMGEMB7	Approved	Hydrocortisone increases the export of Kallikrein-1 (KLK1).	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Magnesium	DMU4ORS	Approved	Magnesium decreases the activity of Kallikrein-1 (KLK1).	[3]
AMG 386	DMQJXL4	Phase 3	AMG 386 decreases the activity of Kallikrein-1 (KLK1).	[3]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the expression of Kallikrein-1 (KLK1).	[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 affects the methylation of Kallikrein-1 (KLK1).	[4]

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] Experimental studies on cortisol-induced hypertension in humans. J Hum Hypertens. 1995 Jun;9(6):395-9.
• [3] The effect of cations on the amidase activity of human tissue kallikrein: 1-linear competitive inhibition by sodium, potassium, calcium and magnesium. 2-linear mixed inhibition by aluminium. J Enzyme Inhib Med Chem. 2004 Aug;19(4):317-25. doi: 10.1080/14756360409162444.
• [4] 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.
• [5] Transcriptome profile analysis of saturated aliphatic aldehydes reveals carbon number-specific molecules involved in pulmonary toxicity. Chem Res Toxicol. 2014 Aug 18;27(8):1362-70.
• [6] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.
• [7] Kallikrein gene delivery improves cardiac reserve and attenuates remodeling after myocardial infarction. Hypertension. 2002 Nov;40(5):653-9. doi: 10.1161/01.hyp.0000036035.41122.99.