Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTBTPR2T)

• DOT Name: Peptidoglycan recognition protein 1 (PGLYRP1)
• Synonyms: Peptidoglycan recognition protein short; PGRP-S
• Gene Name: PGLYRP1
• Related Disease:
  Bacterial infection
  Chronic kidney disease
  Crohn disease
  Gram-positive bacterial infection
  Immunodeficiency
  Inflammatory bowel disease
  Melanoma
  Neoplasm
  Nephropathy
  Psoriasis
  Ulcerative colitis
  Rheumatoid arthritis
  Parkinson disease
• UniProt ID: PGRP1_HUMAN
• PDB ID: 1YCK
• Pfam ID: PF01510
• Sequence:
  MSRRSMLLAWALPSLLRLGAAQETEDPACCSPIVPRNEWKALASECAQHLSLPLRYVVVS
  HTAGSSCNTPASCQQQARNVQHYHMKTLGWCDVGYNFLIGEDGLVYEGRGWNFTGAHSGH
  LWNPMSIGISFMGNYMDRVPTPQAIRAAQGLLACGVAQGALRSNYVLKGHRDVQRTLSPG
  NQLYHLIQNWPHYRSP
• Function: Innate immunity protein that plays several important functions in antimicrobial and antitumor defense systems. Acts as a pattern receptor that binds to murein peptidoglycans (PGN) of Gram-positive bacteria and thus provides bactericidal activity. Forms an equimolar complex with heat shock protein HSPA1A and induces programmed cell death through apoptosis and necroptosis in tumor cell lines by activating the TNFR1 receptor on the target cell membrane. In addition, acts in complex with the Ca(2+)-binding protein S100A4 as a chemoattractant able to induce lymphocyte movement. Mechanistically, this complex acts as a ligand of the chemotactic receptors CCR5 and CXCR3 which are present on the cells of the immune system. Promotes also the activation of lymphocytes that become able to kill virus-infected cells as well as tumor cells by modulating the spectrum of their target-cell specificity. Induction of cytotoxicity on monocyte surface requires interaction with TREM1 receptor.
• Tissue Specificity: Highly expressed in bone marrow. Weak expression found in kidney, liver, small intestine, spleen, thymus, peripheral leukocyte, lung, fetal spleen and neutrophils.
• Reactome Pathway:
  Antimicrobial peptides (R-HSA-6803157)
  Neutrophil degranulation (R-HSA-6798695)

Molecular Interaction Atlas (MIA) of This DOT

13 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Bacterial infection	DIS5QJ9S	Strong	Altered Expression	[1]
Chronic kidney disease	DISW82R7	Strong	Biomarker	[2]
Crohn disease	DIS2C5Q8	Strong	Genetic Variation	[3]
Gram-positive bacterial infection	DISZ44JH	Strong	Biomarker	[4]
Immunodeficiency	DIS093I0	Strong	Biomarker	[5]
Inflammatory bowel disease	DISGN23E	Strong	Genetic Variation	[3]
Melanoma	DIS1RRCY	Strong	Biomarker	[6]
Neoplasm	DISZKGEW	Strong	Biomarker	[7]
Nephropathy	DISXWP4P	Strong	Biomarker	[2]
Psoriasis	DIS59VMN	Strong	Genetic Variation	[8]
Ulcerative colitis	DIS8K27O	Strong	Genetic Variation	[3]
Rheumatoid arthritis	DISTSB4J	moderate	Biomarker	[9]
Parkinson disease	DISQVHKL	Limited	Genetic Variation	[10]

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 Peptidoglycan recognition protein 1 (PGLYRP1).	[11]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Peptidoglycan recognition protein 1 (PGLYRP1).	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Peptidoglycan recognition protein 1 (PGLYRP1).	[12]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Peptidoglycan recognition protein 1 (PGLYRP1).	[13]

References

• [1] Dehydration triggers ecdysone-mediated recognition-protein priming and elevated anti-bacterial immune responses in Drosophila Malpighian tubule renal cells.BMC Biol. 2018 May 31;16(1):60. doi: 10.1186/s12915-018-0532-5.
• [2] Association of the salivary triggering receptor expressed on myeloid cells/its ligand peptidoglycan recognition protein 1 axis with oral inflammation in kidney disease.J Periodontol. 2018 Jan;89(1):117-129. doi: 10.1902/jop.2017.170218.
• [3] Genetic Association of Peptidoglycan Recognition Protein Variants with Inflammatory Bowel Disease.PLoS One. 2013 Jun 19;8(6):e67393. doi: 10.1371/journal.pone.0067393. Print 2013.
• [4] Molecular characteristics of hemoglobins in blood clam and their immune responses to bacterial infection.Int J Biol Macromol. 2017 Jun;99:375-383. doi: 10.1016/j.ijbiomac.2017.02.078. Epub 2017 Feb 24.
• [5] The peptidoglycan recognition protein PGRP-LE regulates the Drosophila immune response against the pathogen Photorhabdus.Microb Pathog. 2019 Nov;136:103664. doi: 10.1016/j.micpath.2019.103664. Epub 2019 Aug 9.
• [6] Phase I/II trial of gene therapy with autologous tumor cells modified with tag7/PGRP-S gene in patients with disseminated solid tumors: miscellaneous tumors.Ann Oncol. 2005 Jan;16(1):162-8. doi: 10.1093/annonc/mdi028.
• [7] FasL and the NKG2D receptor are required for the secretion of the Tag7/PGRP-S-Hsp70 complex by the cytotoxic CD8(+) lymphocytes.IUBMB Life. 2017 Jan;69(1):30-36. doi: 10.1002/iub.1587. Epub 2016 Nov 20.
• [8] Association of psoriasis to PGLYRP and SPRR genes at PSORS4 locus on 1q shows heterogeneity between Finnish, Swedish and Irish families.Exp Dermatol. 2009 Feb;18(2):109-15. doi: 10.1111/j.1600-0625.2008.00769.x. Epub 2008 Jul 17.
• [9] Serum PGLYRP? is a highly discriminatory biomarker for the diagnosis of rheumatoid arthritis.Mol Med Rep. 2019 Jan;19(1):589-594. doi: 10.3892/mmr.2018.9632. Epub 2018 Nov 8.
• [10] Peptidoglycan recognition protein genes and risk of Parkinson's disease.Mov Disord. 2014 Aug;29(9):1171-80. doi: 10.1002/mds.25895. Epub 2014 May 17.
• [11] 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.
• [12] 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.
• [13] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [14] 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.