Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTF9IIXW)

• DOT Name: Protein S100-A12 (S100A12)
• Synonyms: CGRP; Calcium-binding protein in amniotic fluid 1; CAAF1; Calgranulin-C; CAGC; Extracellular newly identified RAGE-binding protein; EN-RAGE; Migration inhibitory factor-related protein 6; MRP-6; p6; Neutrophil S100 protein; S100 calcium-binding protein A12
• Gene Name: S100A12
• UniProt ID: S10AC_HUMAN
• PDB ID: 1E8A; 1GQM; 1ODB; 2M9G; 2WC8; 2WCB; 2WCE; 2WCF
• Pfam ID: PF01023
• Sequence:
  MTKLEEHLEGIVNIFHQYSVRKGHFDTLSKGELKQLLTKELANTIKNIKDKAVIDEIFQG
  LDANQDEQVDFQEFISLVAIALKAAHYHTHKE
• Function: S100A12 is a calcium-, zinc- and copper-binding protein which plays a prominent role in the regulation of inflammatory processes and immune response. Its pro-inflammatory activity involves recruitment of leukocytes, promotion of cytokine and chemokine production, and regulation of leukocyte adhesion and migration. Acts as an alarmin or a danger associated molecular pattern (DAMP) molecule and stimulates innate immune cells via binding to receptor for advanced glycation endproducts (AGER). Binding to AGER activates the MAP-kinase and NF-kappa-B signaling pathways leading to production of pro-inflammatory cytokines and up-regulation of cell adhesion molecules ICAM1 and VCAM1. Acts as a monocyte and mast cell chemoattractant. Can stimulate mast cell degranulation and activation which generates chemokines, histamine and cytokines inducing further leukocyte recruitment to the sites of inflammation. Can inhibit the activity of matrix metalloproteinases; MMP2, MMP3 and MMP9 by chelating Zn(2+) from their active sites. Possesses filariacidal and filariastatic activity. Calcitermin possesses antifungal activity against C.albicans and is also active against E.coli and P.aeruginosa but not L.monocytogenes and S.aureus.
• Tissue Specificity: Predominantly expressed by neutrophils, monocytes and activated macrophages. Expressed by eosinophils and macrophages in asthmatic airways in regions where mast cells accumulate. Found in high concentrations in the serum of patients suffering from various inflammatory disorders, such as rheumatoid arthritis, psoriatic arthritis, Crohn's disease, ulcerative colitis, and Kawasaki disease.
• Reactome Pathway:
  Neutrophil degranulation (R-HSA-6798695)
  Advanced glycosylation endproduct receptor signaling (R-HSA-879415)
  TRAF6 mediated NF-kB activation (R-HSA-933542)
  TAK1-dependent IKK and NF-kappa-B activation (R-HSA-445989)

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Protein S100-A12 (S100A12).	[1]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Protein S100-A12 (S100A12).	[2]
Arsenic	DMTL2Y1	Approved	Arsenic affects the expression of Protein S100-A12 (S100A12).	[3]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Protein S100-A12 (S100A12).	[4]
Hydroquinone	DM6AVR4	Approved	Hydroquinone increases the expression of Protein S100-A12 (S100A12).	[5]
Miglitol	DMXBQAM	Approved	Miglitol decreases the expression of Protein S100-A12 (S100A12).	[6]
Arecoline	DMFJZK3	Phase 1	Arecoline decreases the expression of Protein S100-A12 (S100A12).	[8]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Protein S100-A12 (S100A12).	[9]
D-glucose	DMMG2TO	Investigative	D-glucose increases the expression of Protein S100-A12 (S100A12).	[10]

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 decreases the methylation of Protein S100-A12 (S100A12).	[7]

References

• [1] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [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] Prenatal arsenic exposure and shifts in the newborn proteome: interindividual differences in tumor necrosis factor (TNF)-responsive signaling. Toxicol Sci. 2014 Jun;139(2):328-37. doi: 10.1093/toxsci/kfu053. Epub 2014 Mar 27.
• [4] Peripheral blood expression of nuclear factor-kappab-regulated genes is associated with rheumatoid arthritis disease activity and responds differentially to anti-tumor necrosis factor-alpha versus methotrexate. J Rheumatol. 2007 Sep;34(9):1817-22. Epub 2007 Aug 1.
• [5] Retinoic acid and hydroquinone induce inverse expression patterns on cornified envelope-associated proteins: implication in skin irritation. J Dermatol Sci. 2014 Nov;76(2):112-9. doi: 10.1016/j.jdermsci.2014.08.003. Epub 2014 Aug 26.
• [6] The -glucosidase inhibitor miglitol decreases glucose fluctuations and inflammatory cytokine gene expression in peripheral leukocytes of Japanese patients with type 2 diabetes mellitus. Metabolism. 2010 Dec;59(12):1816-22. doi: 10.1016/j.metabol.2010.06.006. Epub 2010 Jul 29.
• [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.
• [8] Characterization of arecoline-induced effects on cytotoxicity in normal human gingival fibroblasts by global gene expression profiling. Toxicol Sci. 2007 Nov;100(1):66-74.
• [9] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [10] Hyperglycemia-induced reactive oxygen species increase expression of the receptor for advanced glycation end products (RAGE) and RAGE ligands. Diabetes. 2010 Jan;59(1):249-55. doi: 10.2337/db09-0801. Epub 2009 Oct 15.