Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT1P16B5)

• DOT Name: Solute carrier family 15 member 1 (SLC15A1)
• Synonyms: Intestinal H(+)/peptide cotransporter; Oligopeptide transporter, small intestine isoform; Peptide transporter 1
• Gene Name: SLC15A1
• UniProt ID: S15A1_HUMAN
• PDB ID: 7PMW; 7PMX; 7PN1
• Pfam ID: PF00854
• Sequence:
  MGMSKSHSFFGYPLSIFFIVVNEFCERFSYYGMRAILILYFTNFISWDDNLSTAIYHTFV
  ALCYLTPILGALIADSWLGKFKTIVSLSIVYTIGQAVTSVSSINDLTDHNHDGTPDSLPV
  HVVLSLIGLALIALGTGGIKPCVSAFGGDQFEEGQEKQRNRFFSIFYLAINAGSLLSTII
  TPMLRVQQCGIHSKQACYPLAFGVPAALMAVALIVFVLGSGMYKKFKPQGNIMGKVAKCI
  GFAIKNRFRHRSKAFPKREHWLDWAKEKYDERLISQIKMVTRVMFLYIPLPMFWALFDQQ
  GSRWTLQATTMSGKIGALEIQPDQMQTVNAILIVIMVPIFDAVLYPLIAKCGFNFTSLKK
  MAVGMVLASMAFVVAAIVQVEIDKTLPVFPKGNEVQIKVLNIGNNTMNISLPGEMVTLGP
  MSQTNAFMTFDVNKLTRINISSPGSPVTAVTDDFKQGQRHTLLVWAPNHYQVVKDGLNQK
  PEKGENGIRFVNTFNELITITMSGKVYANISSYNASTYQFFPSGIKGFTISSTEIPPQCQ
  PNFNTFYLEFGSAYTYIVQRKNDSCPEVKVFEDISANTVNMALQIPQYFLLTCGEVVFSV
  TGLEFSYSQAPSNMKSVLQAGWLLTVAVGNIIVLIVAGAGQFSKQWAEYILFAALLLVVC
  VIFAIMARFYTYINPAEIEAQFDEDEKKNRLEKSNPYFMSGANSQKQM
• Function: Electrogenic proton-coupled amino-acid transporter that transports oligopeptides of 2 to 4 amino acids with a preference for dipeptides. Transports neutral and monovalently charged peptides with a proton to peptide stoichiometry of 1:1 or 2:1. Primarily responsible for the absorption of dietary di- and tripeptides from the small intestinal lumen. Mediates transepithelial transport of muramyl and N-formylated bacterial dipeptides contributing to recognition of pathogenic bacteria by the mucosal immune system.
• Tissue Specificity: Expressed in small intestine.
• KEGG Pathway: Protein digestion and absorption (hsa04974)
• Reactome Pathway: Proton/oligopeptide cotransporters (R-HSA-427975)

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of Solute carrier family 15 member 1 (SLC15A1).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Solute carrier family 15 member 1 (SLC15A1).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Solute carrier family 15 member 1 (SLC15A1).	[3]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Solute carrier family 15 member 1 (SLC15A1).	[4]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Solute carrier family 15 member 1 (SLC15A1).	[5]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil decreases the expression of Solute carrier family 15 member 1 (SLC15A1).	[6]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of Solute carrier family 15 member 1 (SLC15A1).	[7]
Azathioprine	DMMZSXQ	Approved	Azathioprine decreases the expression of Solute carrier family 15 member 1 (SLC15A1).	[8]
Rifampicin	DM5DSFZ	Approved	Rifampicin decreases the expression of Solute carrier family 15 member 1 (SLC15A1).	[9]
Liothyronine	DM6IR3P	Approved	Liothyronine decreases the expression of Solute carrier family 15 member 1 (SLC15A1).	[11]
Repaglinide	DM5SXUV	Approved	Repaglinide decreases the activity of Solute carrier family 15 member 1 (SLC15A1).	[12]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Solute carrier family 15 member 1 (SLC15A1).	[13]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the expression of Solute carrier family 15 member 1 (SLC15A1).	[11]
PIRINIXIC ACID	DM82Y75	Preclinical	PIRINIXIC ACID increases the expression of Solute carrier family 15 member 1 (SLC15A1).	[15]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Solute carrier family 15 member 1 (SLC15A1).	[16]
[3H]GlySar	DMFEYLS	Investigative	[3H]GlySar decreases the activity of Solute carrier family 15 member 1 (SLC15A1).	[17]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ibuprofen	DM8VCBE	Approved	Ibuprofen affects the binding of Solute carrier family 15 member 1 (SLC15A1).	[10]
Benzoic acid	DMKB9FI	Approved	Benzoic acid affects the binding of Solute carrier family 15 member 1 (SLC15A1).	[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 increases the methylation of Solute carrier family 15 member 1 (SLC15A1).	[14]

References

• [1] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [2] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [3] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [4] Arsenic suppresses gene expression in promyelocytic leukemia cells partly through Sp1 oxidation. Blood. 2005 Jul 1;106(1):304-10.
• [5] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [6] Regulation of human peptide transporter 1 (PEPT1) in gastric cancer cells by anticancer drugs. Cancer Lett. 2005 Dec 8;230(1):72-80.
• [7] Temporal changes in gene expression in the skin of patients treated with isotretinoin provide insight into its mechanism of action. Dermatoendocrinol. 2009 May;1(3):177-87.
• [8] Severe villus atrophy and chronic malabsorption induced by azathioprine. Gastroenterology. 2003 Jun;124(7):1950-7.
• [9] Rifampin Regulation of Drug Transporters Gene Expression and the Association of MicroRNAs in Human Hepatocytes. Front Pharmacol. 2016 Apr 26;7:111.
• [10] Affinity and translocation relationships via hPEPT1 of H-X aa-Ser-OH dipeptides: evaluation of H-Phe-Ser-OH as a pro-moiety for ibuprofen and benzoic acid prodrugs. Eur J Pharm Biopharm. 2011 Feb;77(2):327-31. doi: 10.1016/j.ejpb.2010.12.009. Epub 2010 Dec 13.
• [11] Enhancement effect of resveratrol on the intestinal absorption of bestatin by regulating PEPT1, MDR1 and MRP2 in vivo and in vitro. Int J Pharm. 2015 Nov 10;495(1):588-598. doi: 10.1016/j.ijpharm.2015.09.042. Epub 2015 Sep 21.
• [12] In vitro and pharmacophore-based discovery of novel hPEPT1 inhibitors. Pharm Res. 2005 Apr;22(4):512-7. doi: 10.1007/s11095-005-2505-y. Epub 2005 Apr 7.
• [13] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [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.
• [15] Induction of intestinal peptide transporter 1 expression during fasting is mediated via peroxisome proliferator-activated receptor alpha. Am J Physiol Gastrointest Liver Physiol. 2006 Nov;291(5):G851-6. doi: 10.1152/ajpgi.00171.2006. Epub 2006 Jun 1.
• [16] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [17] Absorption of lisdexamfetamine dimesylate and its enzymatic conversion to d-amphetamine. Neuropsychiatr Dis Treat. 2010 Jun 24;6:317-27.