Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTLYEES9)

• DOT Name: Transient receptor potential cation channel subfamily M member 5 (TRPM5)
• Synonyms: Long transient receptor potential channel 5; LTrpC-5; LTrpC5; MLSN1- and TRP-related gene 1 protein
• Gene Name: TRPM5
• UniProt ID: TRPM5_HUMAN
• Pfam ID: PF00520 ; PF18139
• Sequence:
  MQDVQGPRPGSPGDAEDRRELGLHRGEVNFGGSGKKRGKFVRVPSGVAPSVLFDLLLAEW
  HLPAPNLVVSLVGEEQPFAMKSWLRDVLRKGLVKAAQSTGAWILTSALRVGLARHVGQAV
  RDHSLASTSTKVRVVAVGMASLGRVLHRRILEEAQEDFPVHYPEDDGGSQGPLCSLDSNL
  SHFILVEPGPPGKGDGLTELRLRLEKHISEQRAGYGGTGSIEIPVLCLLVNGDPNTLERI
  SRAVEQAAPWLILVGSGGIADVLAALVNQPHLLVPKVAEKQFKEKFPSKHFSWEDIVRWT
  KLLQNITSHQHLLTVYDFEQEGSEELDTVILKALVKACKSHSQEPQDYLDELKLAVAWDR
  VDIAKSEIFNGDVEWKSCDLEEVMVDALVSNKPEFVRLFVDNGADVADFLTYGRLQELYR
  SVSRKSLLFDLLQRKQEEARLTLAGLGTQQAREPPAGPPAFSLHEVSRVLKDFLQDACRG
  FYQDGRPGDRRRAEKGPAKRPTGQKWLLDLNQKSENPWRDLFLWAVLQNRHEMATYFWAM
  GQEGVAAALAACKILKEMSHLETEAEAARATREAKYERLALDLFSECYSNSEARAFALLV
  RRNRCWSKTTCLHLATEADAKAFFAHDGVQAFLTRIWWGDMAAGTPILRLLGAFLCPALV
  YTNLITFSEEAPLRTGLEDLQDLDSLDTEKSPLYGLQSRVEELVEAPRAQGDRGPRAVFL
  LTRWRKFWGAPVTVFLGNVVMYFAFLFLFTYVLLVDFRPPPQGPSGPEVTLYFWVFTLVL
  EEIRQGFFTDEDTHLVKKFTLYVGDNWNKCDMVAIFLFIVGVTCRMLPSAFEAGRTVLAM
  DFMVFTLRLIHIFAIHKQLGPKIIVVERMMKDVFFFLFFLSVWLVAYGVTTQALLHPHDG
  RLEWIFRRVLYRPYLQIFGQIPLDEIDEARVNCSTHPLLLEDSPSCPSLYANWLVILLLV
  TFLLVTNVLLMNLLIAMFSYTFQVVQGNADMFWKFQRYNLIVEYHERPALAPPFILLSHL
  SLTLRRVFKKEAEHKREHLERDLPDPLDQKVVTWETVQKENFLSKMEKRRRDSEGEVLRK
  TAHRVDFIAKYLGGLREQEKRIKCLESQINYCSVLVSSVADVLAQGGGPRSSQHCGEGSQ
  LVAADHRGGLDGWEQPGAGQPPSDT
• Function: Voltage-modulated Ca(2+)-activated, monovalent cation channel (VCAM) that mediates a transient membrane depolarization and plays a central role in taste transduction. Monovalent-specific, non-selective cation channel that mediates the transport of Na(+), K(+) and Cs(+) ions equally well. Activated directly by increases in intracellular Ca(2+), but is impermeable to it. Gating is voltage-dependent and displays rapid activation and deactivation kinetics upon channel stimulation even during sustained elevations in Ca(2+). Also activated by a fast intracellular Ca(2+) increase in response to inositol 1,4,5-triphosphate-producing receptor agonists. The channel is blocked by extracellular acidification. External acidification has 2 effects, a fast reversible block of the current and a slower irreversible enhancement of current inactivation. Is a highly temperature-sensitive, heat activated channel showing a steep increase of inward currents at temperatures between 15 and 35 degrees Celsius. Heat activation is due to a shift of the voltage-dependent activation curve to negative potentials. Activated by arachidonic acid in vitro. May be involved in perception of bitter, sweet and umami tastes. May also be involved in sensing semiochemicals.
• Tissue Specificity: Strongly expressed in fetal brain, liver and kidney, and in adult prostate, testis, ovary, colon and peripheral blood leukocytes. Also expressed in a large proportion of Wilms' tumors and rhabdomyosarcomas. In monochromosomal cell lines shows exclusive paternal expression.
• KEGG Pathway: Taste transduction (hsa04742)
• Reactome Pathway:
  Sensory perception of sweet, bitter, and umami (glutamate) taste (R-HSA-9717207)
  TRP channels (R-HSA-3295583)

Molecular Interaction Atlas (MIA) of This DOT

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 Transient receptor potential cation channel subfamily M member 5 (TRPM5).	[1]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Transient receptor potential cation channel subfamily M member 5 (TRPM5).	[5]

5 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 Transient receptor potential cation channel subfamily M member 5 (TRPM5).	[2]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Transient receptor potential cation channel subfamily M member 5 (TRPM5).	[3]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Transient receptor potential cation channel subfamily M member 5 (TRPM5).	[4]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Transient receptor potential cation channel subfamily M member 5 (TRPM5).	[6]
9-phenanthrol	DMJFBQ1	Investigative	9-phenanthrol decreases the activity of Transient receptor potential cation channel subfamily M member 5 (TRPM5).	[7]

References

• [1] 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.
• [2] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [3] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [4] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [5] 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.
• [6] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [7] 9-phenanthrol inhibits human TRPM4 but not TRPM5 cationic channels. Br J Pharmacol. 2008 Apr;153(8):1697-705.