Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT0BVQRB)

• DOT Name: Regenerating islet-derived protein 3-alpha (REG3A)
• Synonyms: REG-3-alpha; Hepatointestinal pancreatic protein; HIP/PAP; Human proislet peptide; HIP; Pancreatitis-associated protein 1; Regenerating islet-derived protein III-alpha; Reg III-alpha
• Gene Name: REG3A
• UniProt ID: REG3A_HUMAN
• PDB ID: 1UV0; 2GO0; 4MTH
• Pfam ID: PF00059
• Sequence:
  MLPPMALPSVSWMLLSCLMLLSQVQGEEPQRELPSARIRCPKGSKAYGSHCYALFLSPKS
  WTDADLACQKRPSGNLVSVLSGAEGSFVSSLVKSIGNSYSYVWIGLHDPTQGTEPNGEGW
  EWSSSDVMNYFAWERNPSTISSPGHCASLSRSTAFLRWKDYNCNVRLPYVCKFTD
• Function: [Regenerating islet-derived protein 3-alpha 15 kDa form]: Bactericidal C-type lectin which acts exclusively against Gram-positive bacteria and mediates bacterial killing by binding to surface-exposed carbohydrate moieties of peptidoglycan. Binds membrane phospholipids and kills bacteria by forming a hexameric membrane-permeabilizing oligomeric pore ; Acts as a hormone in response to different stimuli like anti-inflammatory signals, such as IL17A, or gut microbiome. Secreted by different cell types to activate its receptor EXTL3 and induce cell specific signaling pathways. Induced by IL17A in keratinocytes, regulates keratinocyte proliferation and differentiation after skin injury via activation of EXTL3-PI3K-AKT signaling pathway. In parallel, inhibits skin inflammation through the inhibition of inflammatory cytokines such as IL6 and TNF. In pancreas, is able to permealize beta-cells membrane and stimulate their proliferation ; [Regenerating islet-derived protein 3-alpha 16.5 kDa form]: Has bacteriostatic activity.
• Tissue Specificity: Expressed by keratinocytes . Highly expressed in epidermal keratinocytes of psoriasis patients (at protein level) . Constitutively expressed in intestine. Low expression is found in healthy pancreas. Overexpressed during the acute phase of pancreatitis and in some patients with chronic pancreatitis .
• Reactome Pathway: Antimicrobial peptides (R-HSA-6803157)

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
Ethanol	DMDRQZU	Approved	Regenerating islet-derived protein 3-alpha (REG3A) increases the Pancreatic disorder ADR of Ethanol.	[4]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Regenerating islet-derived protein 3-alpha (REG3A).	[1]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Regenerating islet-derived protein 3-alpha (REG3A).	[2]
Gemcitabine	DMSE3I7	Approved	Gemcitabine decreases the expression of Regenerating islet-derived protein 3-alpha (REG3A).	[3]

References

• [1] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [2] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [3] Effect of gemcitabine on the expression of apoptosis-related genes in human pancreatic cancer cells. World J Gastroenterol. 2006 Mar 14;12(10):1597-602. doi: 10.3748/wjg.v12.i10.1597.
• [4] ADReCS-Target: target profiles for aiding drug safety research and application. Nucleic Acids Res. 2018 Jan 4;46(D1):D911-D917. doi: 10.1093/nar/gkx899.