Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTDAOST4)

• DOT Name: Prestin (SLC26A5)
• Synonyms: Solute carrier family 26 member 5
• Gene Name: SLC26A5
• Related Disease:
  Autosomal recessive nonsyndromic hearing loss 61
  Hearing loss, autosomal recessive
  Nonsyndromic genetic hearing loss
• UniProt ID: S26A5_HUMAN
• PDB ID: 7LGU; 7LGW; 7LH2; 7LH3
• Pfam ID: PF01740 ; PF00916
• Sequence:
  MDHAEENEILAATQRYYVERPIFSHPVLQERLHTKDKVPDSIADKLKQAFTCTPKKIRNI
  IYMFLPITKWLPAYKFKEYVLGDLVSGISTGVLQLPQGLAFAMLAAVPPIFGLYSSFYPV
  IMYCFLGTSRHISIGPFAVISLMIGGVAVRLVPDDIVIPGGVNATNGTEARDALRVKVAM
  SVTLLSGIIQFCLGVCRFGFVAIYLTEPLVRGFTTAAAVHVFTSMLKYLFGVKTKRYSGI
  FSVVYSTVAVLQNVKNLNVCSLGVGLMVFGLLLGGKEFNERFKEKLPAPIPLEFFAVVMG
  TGISAGFNLKESYNVDVVGTLPLGLLPPANPDTSLFHLVYVDAIAIAIVGFSVTISMAKT
  LANKHGYQVDGNQELIALGLCNSIGSLFQTFSISCSLSRSLVQEGTGGKTQLAGCLASLM
  ILLVILATGFLFESLPQAVLSAIVIVNLKGMFMQFSDLPFFWRTSKIELTIWLTTFVSSL
  FLGLDYGLITAVIIALLTVIYRTQSPSYKVLGKLPETDVYIDIDAYEEVKEIPGIKIFQI
  NAPIYYANSDLYSNALKRKTGVNPAVIMGARRKAMRKYAKEVGNANMANATVVKADAEVD
  GEDATKPEEEDGEVKYPPIVIKSTFPEEMQRFMPPGDNVHTVILDFTQVNFIDSVGVKTL
  AGIVKEYGDVGIYVYLAGCSAQVVNDLTRNRFFENPALWELLFHSIHDAVLGSQLREALA
  EQEASAPPSQEDLEPNATPATPEA
• Function: Voltage-sensitive motor protein that drives outer hair cell (OHC) electromotility (eM) and participates in sound amplification in the hearing organ. Converts changes in the transmembrane electric potential into mechanical displacements resulting in the coupling of its expansion to movement of a charged voltage sensor across the lipid membrane. The nature of the voltage sensor is not completely clear, and two models compete. In the first model, acts as an incomplete transporter where intracellular chloride anion acts as extrinsic voltage sensor that drives conformational change in the protein which is sufficient to produce a length change in the plane of the membrane and hence in the length of the OHC. The second model in which multiple charged amino acid residues are distributed at the intracellular and extracellular membrane interfaces that form an intrinsic voltage sensor, whose movement produces the non-linear capacitance (NLC). However, the effective voltage sensor may be the result of a hybrid voltage sensor, assembled from intrinsic charge (charged residues) and extrinsic charge (bound anion). Notably, binding of anions to the anion-binding pocket partially neutralizes the intrinsic positive charge rather than to form an electrically negative sensor, therefore remaining charge may serve as voltage sensor that, after depolarization, moves from down (expanded state) to up (contracted) conformation, which is accompanied by an eccentric contraction of the intermembrane cross-sectional area of the protein as well as a major increase in the hydrophobic thickness of the protein having as consequences the plasma membrane thickening and the cell contraction after membrane depolarization. The anion-binding pocket transits from the inward-open (Down) state, where it is exposed toward the intracellular solvent in the absence of anion, to the occluded (Up) state upon anion binding. Salicylate competes for the anion-binding site and inhibits the voltage-sensor movement, and therefore inhibits the charge transfer and electromotility by displacing Cl(-) from the anion-binding site and by preventing the structural transitions to the contracted state. In addition, can act as a weak Cl(-)/HCO3(-) antiporter across the cell membrane and so regulate the intracellular pH of the outer hair cells (OHCs), while firstly found as being unable to mediate electrogenic anion transport. Moreover, supports a role in cardiac mechanical amplification serving as an elastic element to enhance the actomyosin- based sarcomere contraction system.
• Reactome Pathway: Sensory processing of sound by outer hair cells of the cochlea (R-HSA-9662361)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Autosomal recessive nonsyndromic hearing loss 61	DISDW504	Strong	Autosomal recessive	[1]
Hearing loss, autosomal recessive	DIS8G9R9	Supportive	Autosomal recessive	[2]
Nonsyndromic genetic hearing loss	DISZX61P	Limited	Autosomal recessive	[3]

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 Prestin (SLC26A5).	[4]

References

• [1] Diverse spectrum of rare deafness genes underlies early-childhood hearing loss in Japanese patients: a cross-sectional, multi-center next-generation sequencing study. Orphanet J Rare Dis. 2013 Oct 28;8:172. doi: 10.1186/1750-1172-8-172.
• [2] Genetic Hearing Loss Overview. 1999 Feb 14 [updated 2023 Sep 28]. 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.
• [3] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [4] 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.