Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTDV7YES)

• DOT Name: Solute carrier family 15 member 2 (SLC15A2)
• Synonyms: Kidney H(+)/peptide cotransporter; Oligopeptide transporter, kidney isoform; Peptide transporter 2
• Gene Name: SLC15A2
• UniProt ID: S15A2_HUMAN
• PDB ID: 6EZI; 7PMY
• Pfam ID: PF00854
• Sequence:
  MNPFQKNESKETLFSPVSIEEVPPRPPSPPKKPSPTICGSNYPLSIAFIVVNEFCERFSY
  YGMKAVLILYFLYFLHWNEDTSTSIYHAFSSLCYFTPILGAAIADSWLGKFKTIIYLSLV
  YVLGHVIKSLGALPILGGQVVHTVLSLIGLSLIALGTGGIKPCVAAFGGDQFEEKHAEER
  TRYFSVFYLSINAGSLISTFITPMLRGDVQCFGEDCYALAFGVPGLLMVIALVVFAMGSK
  IYNKPPPEGNIVAQVFKCIWFAISNRFKNRSGDIPKRQHWLDWAAEKYPKQLIMDVKALT
  RVLFLYIPLPMFWALLDQQGSRWTLQAIRMNRNLGFFVLQPDQMQVLNPLLVLIFIPLFD
  FVIYRLVSKCGINFSSLRKMAVGMILACLAFAVAAAVEIKINEMAPAQPGPQEVFLQVLN
  LADDEVKVTVVGNENNSLLIESIKSFQKTPHYSKLHLKTKSQDFHFHLKYHNLSLYTEHS
  VQEKNWYSLVIREDGNSISSMMVKDTESRTTNGMTTVRFVNTLHKDVNISLSTDTSLNVG
  EDYGVSAYRTVQRGEYPAVHCRTEDKNFSLNLGLLDFGAAYLFVITNNTNQGLQAWKIED
  IPANKMSIAWQLPQYALVTAGEVMFSVTGLEFSYSQAPSSMKSVLQAAWLLTIAVGNIIV
  LVVAQFSGLVQWAEFILFSCLLLVICLIFSIMGYYYVPVKTEDMRGPADKHIPHIQGNMI
  KLETKKTKL
• Function: Proton-coupled amino-acid transporter that transports oligopeptides of 2 to 4 amino acids with a preference for dipeptides. Transports neutral and anionic dipeptides with a proton to peptide stoichiometry of 2:1 or 3:1. In kidney, involved in the absorption of circulating di- and tripeptides from the glomerular filtrate. Can also transport beta-lactam antibiotics, such as the aminocephalosporin cefadroxil, and other antiviral and anticancer drugs. Transports the dipeptide-like aminopeptidase inhibitor bestatin. Also able to transport carnosine. Involved in innate immunity by promoting the detection of microbial pathogens by NOD-like receptors (NLRs). Mediates transport of bacterial peptidoglycans across the plasma membrane or, in macrophages, the phagosome membrane: catalyzes the transport of certain bacterial peptidoglycans, such as muramyl dipeptide (MDP), the NOD2 ligand.
• Tissue Specificity: Expressed in kidney . Not detected in intestine . Highly expressed in macrophages .
• Reactome Pathway: Proton/oligopeptide cotransporters (R-HSA-427975)

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Drug Response of 3 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Temozolomide	DMKECZD	Approved	Solute carrier family 15 member 2 (SLC15A2) affects the response to substance of Temozolomide.	[12]
DTI-015	DMXZRW0	Approved	Solute carrier family 15 member 2 (SLC15A2) affects the response to substance of DTI-015.	[12]
Warfarin	DMJYCVW	Approved	Solute carrier family 15 member 2 (SLC15A2) affects the response to substance of Warfarin.	[13]

This DOT Affected the Regulation of Drug Effects of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
[3H]GlySar	DMFEYLS	Investigative	Solute carrier family 15 member 2 (SLC15A2) increases the uptake of [3H]GlySar.	[14]

11 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 Solute carrier family 15 member 2 (SLC15A2).	[1]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Solute carrier family 15 member 2 (SLC15A2).	[2]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Solute carrier family 15 member 2 (SLC15A2).	[3]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Solute carrier family 15 member 2 (SLC15A2).	[3]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Solute carrier family 15 member 2 (SLC15A2).	[4]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of Solute carrier family 15 member 2 (SLC15A2).	[5]
Progesterone	DMUY35B	Approved	Progesterone decreases the expression of Solute carrier family 15 member 2 (SLC15A2).	[6]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Solute carrier family 15 member 2 (SLC15A2).	[7]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of Solute carrier family 15 member 2 (SLC15A2).	[8]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Solute carrier family 15 member 2 (SLC15A2).	[10]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Solute carrier family 15 member 2 (SLC15A2).	[11]

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 2 (SLC15A2).	[9]

References

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• [2] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [3] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [4] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [5] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [6] Endometrial receptivity is affected in women with high circulating progesterone levels at the end of the follicular phase: a functional genomics analysis. Hum Reprod. 2011 Jul;26(7):1813-25.
• [7] LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
• [8] Dose- and time-dependent transcriptional response of Ishikawa cells exposed to genistein. Toxicol Sci. 2016 May;151(1):71-87.
• [9] 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.
• [10] Loss of TRIM33 causes resistance to BET bromodomain inhibitors through MYC- and TGF-beta-dependent mechanisms. Proc Natl Acad Sci U S A. 2016 Aug 2;113(31):E4558-66.
• [11] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [12] Tumor necrosis factor-alpha-induced protein 3 as a putative regulator of nuclear factor-kappaB-mediated resistance to O6-alkylating agents in human glioblastomas. J Clin Oncol. 2006 Jan 10;24(2):274-87. doi: 10.1200/JCO.2005.02.9405. Epub 2005 Dec 19.
• [13] Identification of two novel genes SLC15A2 and SLCO1B3 associated with maintenance dose variability of warfarin in a Chinese population. Sci Rep. 2017 Dec 12;7(1):17379. doi: 10.1038/s41598-017-17731-1.
• [14] Completing the Enalaprilat Excretion Pathway-Renal Handling by the Proximal Tubule. Pharmaceutics. 2020 Sep 30;12(10):935. doi: 10.3390/pharmaceutics12100935.