Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTM5EC0O)

• DOT Name: Sialin (SLC17A5)
• Synonyms: H(+)/nitrate cotransporter; H(+)/sialic acid cotransporter; AST; Membrane glycoprotein HP59; Solute carrier family 17 member 5; Vesicular excitatory amino acid transporter; VEAT
• Gene Name: SLC17A5
• Related Disease:
  Free sialic acid storage disease
  Salla disease
  Free sialic acid storage disease, infantile form
  Intermediate severe Salla disease
• UniProt ID: S17A5_HUMAN
• PDB ID: 8DWI
• Pfam ID: PF07690
• Sequence:
  MRSPVRDLARNDGEESTDRTPLLPGAPRAEAAPVCCSARYNLAILAFFGFFIVYALRVNL
  SVALVDMVDSNTTLEDNRTSKACPEHSAPIKVHHNQTGKKYQWDAETQGWILGSFFYGYI
  ITQIPGGYVASKIGGKMLLGFGILGTAVLTLFTPIAADLGVGPLIVLRALEGLGEGVTFP
  AMHAMWSSWAPPLERSKLLSISYAGAQLGTVISLPLSGIICYYMNWTYVFYFFGTIGIFW
  FLLWIWLVSDTPQKHKRISHYEKEYILSSLRNQLSSQKSVPWVPILKSLPLWAIVVAHFS
  YNWTFYTLLTLLPTYMKEILRFNVQENGFLSSLPYLGSWLCMILSGQAADNLRAKWNFST
  LCVRRIFSLIGMIGPAVFLVAAGFIGCDYSLAVAFLTISTTLGGFCSSGFSINHLDIAPS
  YAGILLGITNTFATIPGMVGPVIAKSLTPDNTVGEWQTVFYIAAAINVFGAIFFTLFAKG
  EVQNWALNDHHGHRH
• Function: Multifunctional anion transporter that operates via two distinct transport mechanisms, namely proton-coupled anion cotransport and membrane potential-dependent anion transport. Electroneutral proton-coupled acidic monosaccharide symporter, with a sugar to proton stoichiometry of 1:1. Exports glucuronic acid and free sialic acid derived from sialoglycoconjugate degradation out of lysosomes, driven by outwardly directed lysosomal pH gradient. May regulate lysosome function and metabolism of sialylated conjugates that impact oligodendrocyte lineage differentiation and myelinogenesis in the central nervous system. Electrogenic proton-coupled nitrate symporter that transports nitrate ions across the basolateral membrane of salivary gland acinar cells, with nitrate to proton stoichiometry of 2:1. May contribute to nitrate clearance from serum by salivary glands, where it is further concentrated and secreted in the saliva. Uses membrane potential to drive the uptake of acidic amino acids and peptides into synaptic vesicles. Responsible for synaptic vesicular storage of L-aspartate and L-glutamate in pinealocytes as well as vesicular uptake of N-acetyl-L-aspartyl-L-glutamate neuropeptide, relevant to aspartegic-associated glutamatergic neurotransmission and activation of metabotropic receptors that inhibit subsequent transmitter release ; Receptor for CM101, a polysaccharide produced by group B Streptococcus with antipathoangiogenic properties.
• Tissue Specificity: In the adult, detected in placenta, kidney and pancreas. Abundant in the endothelial cells of tumors from ovary, colon, breast and lung, but is not detected in endothelial cells from the corresponding normal tissues . Highly expressed in salivary glands and liver, with lower levels of expression in brain, spleen kidney, muscle and pancreas. Expressed in acinar cells of salivary glands (at protein level) .
• KEGG Pathway: Lysosome (hsa04142)
• Reactome Pathway:
  Organic anion transporters (R-HSA-428643)
  Defective SLC17A5 causes Salla disease (SD) and ISSD (R-HSA-5619035)
  Sialic acid metabolism (R-HSA-4085001)

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Free sialic acid storage disease	DISBHKLW	Definitive	Autosomal recessive	[1]
Salla disease	DISA4PBW	Definitive	Autosomal recessive	[1]
Free sialic acid storage disease, infantile form	DIS22WWJ	Strong	Autosomal recessive	[2]
Intermediate severe Salla disease	DISK1HCT	Supportive	Autosomal recessive	[3]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
3-iodothyronamine	DM3L0F8	Investigative	Sialin (SLC17A5) affects the uptake of 3-iodothyronamine.	[20]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Sialin (SLC17A5).	[4]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Sialin (SLC17A5).	[5]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Sialin (SLC17A5).	[6]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Sialin (SLC17A5).	[7]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Sialin (SLC17A5).	[7]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Sialin (SLC17A5).	[8]
Marinol	DM70IK5	Approved	Marinol decreases the expression of Sialin (SLC17A5).	[9]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of Sialin (SLC17A5).	[10]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Sialin (SLC17A5).	[11]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Sialin (SLC17A5).	[13]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Sialin (SLC17A5).	[14]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Sialin (SLC17A5).	[16]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Sialin (SLC17A5).	[17]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Sialin (SLC17A5).	[18]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of Sialin (SLC17A5).	[6]
PP-242	DM2348V	Investigative	PP-242 decreases the expression of Sialin (SLC17A5).	[19]

2 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 affects the methylation of Sialin (SLC17A5).	[12]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Sialin (SLC17A5).	[15]

References

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• [2] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [3] Free Sialic Acid Storage Disorders. 2003 Jun 13 [updated 2020 Jan 23]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews(?) [Internet]. Seattle (WA): University of Washington, Seattle; 1993C2024.
• [4] 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.
• [5] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [6] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [7] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [8] 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.
• [9] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [10] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [11] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [12] Effect of aflatoxin B(1), benzo[a]pyrene, and methapyrilene on transcriptomic and epigenetic alterations in human liver HepaRG cells. Food Chem Toxicol. 2018 Nov;121:214-223. doi: 10.1016/j.fct.2018.08.034. Epub 2018 Aug 26.
• [13] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [14] 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.
• [15] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [16] Alternatives for the worse: Molecular insights into adverse effects of bisphenol a and substitutes during human adipocyte differentiation. Environ Int. 2021 Nov;156:106730. doi: 10.1016/j.envint.2021.106730. Epub 2021 Jun 27.
• [17] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [18] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [19] Marine biogenics in sea spray aerosols interact with the mTOR signaling pathway. Sci Rep. 2019 Jan 24;9(1):675.
• [20] Identification and characterization of 3-iodothyronamine intracellular transport. Endocrinology. 2009 Apr;150(4):1991-9.