General Information of Drug Off-Target (DOT) (ID: OTX8N6YO)

DOT Name ADP/ATP translocase 4 (SLC25A31)
Synonyms ADP,ATP carrier protein 4; Adenine nucleotide translocator 4; ANT 4; Solute carrier family 25 member 31; Sperm flagellar energy carrier protein
Gene Name SLC25A31
UniProt ID
ADT4_HUMAN
3D Structure
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2D Sequence (FASTA)
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3D Structure (PDB)
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Pfam ID
PF00153
Sequence
MHREPAKKKAEKRLFDASSFGKDLLAGGVAAAVSKTAVAPIERVKLLLQVQASSKQISPE
ARYKGMVDCLVRIPREQGFFSFWRGNLANVIRYFPTQALNFAFKDKYKQLFMSGVNKEKQ
FWRWFLANLASGGAAGATSLCVVYPLDFARTRLGVDIGKGPEERQFKGLGDCIMKIAKSD
GIAGLYQGFGVSVQGIIVYRASYFGAYDTVKGLLPKPKKTPFLVSFFIAQVVTTCSGILS
YPFDTVRRRMMMQSGEAKRQYKGTLDCFVKIYQHEGISSFFRGAFSNVLRGTGGALVLVL
YDKIKEFFHIDIGGR
Function
ADP:ATP antiporter that mediates import of ADP into the mitochondrial matrix for ATP synthesis, and export of ATP out to fuel the cell. Cycles between the cytoplasmic-open state (c-state) and the matrix-open state (m-state): operates by the alternating access mechanism with a single substrate-binding site intermittently exposed to either the cytosolic (c-state) or matrix (m-state) side of the inner mitochondrial membrane. Specifically required during spermatogenesis, probably to mediate ADP:ATP exchange in spermatocytes. Large ATP supplies from mitochondria may be critical for normal progression of spermatogenesis during early stages of meiotic prophase I, including DNA double-strand break repair and chromosomal synapsis. In addition to its ADP:ATP antiporter activity, also involved in mitochondrial uncoupling and mitochondrial permeability transition pore (mPTP) activity. Plays a role in mitochondrial uncoupling by acting as a proton transporter: proton transport uncouples the proton flows via the electron transport chain and ATP synthase to reduce the efficiency of ATP production and cause mitochondrial thermogenesis. Proton transporter activity is inhibited by ADP:ATP antiporter activity, suggesting that SLC25A31/ANT4 acts as a master regulator of mitochondrial energy output by maintaining a delicate balance between ATP production (ADP:ATP antiporter activity) and thermogenesis (proton transporter activity). Proton transporter activity requires free fatty acids as cofactor, but does not transport it. Among nucleotides, may also exchange ADP for dATP and dADP. Also plays a key role in mPTP opening, a non-specific pore that enables free passage of the mitochondrial membranes to solutes of up to 1.5 kDa, and which contributes to cell death. It is however unclear if SLC25A31/ANT4 constitutes a pore-forming component of mPTP or regulates it.
Tissue Specificity
Expressed in brain, liver, sperm and testis . In testis, expressed at higher level in spermatocytes, while it is expressed at lower level in spermatogonial cells . Expressed in erythrocytes (at protein level) .
KEGG Pathway
Calcium sig.ling pathway (hsa04020 )
cGMP-PKG sig.ling pathway (hsa04022 )
Necroptosis (hsa04217 )
Cellular senescence (hsa04218 )
Neutrophil extracellular trap formation (hsa04613 )
Alzheimer disease (hsa05010 )
Parkinson disease (hsa05012 )
Huntington disease (hsa05016 )
Spinocerebellar ataxia (hsa05017 )
Prion disease (hsa05020 )
Pathways of neurodegeneration - multiple diseases (hsa05022 )
Influenza A (hsa05164 )
Human T-cell leukemia virus 1 infection (hsa05166 )
Chemical carcinogenesis - reactive oxygen species (hsa05208 )
Diabetic cardiomyopathy (hsa05415 )

Molecular Interaction Atlas (MIA) of This DOT

Molecular Interaction Atlas (MIA) Jump to Detail Molecular Interaction Atlas of This DOT
1 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 ADP/ATP translocase 4 (SLC25A31). [1]
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2 Drug(s) Affected the Gene/Protein Processing of This DOT
Drug Name Drug ID Highest Status Interaction REF
Benzo(a)pyrene DMN7J43 Phase 1 Benzo(a)pyrene increases the mutagenesis of ADP/ATP translocase 4 (SLC25A31). [2]
AHPN DM8G6O4 Investigative AHPN decreases the activity of ADP/ATP translocase 4 (SLC25A31). [3]
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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 Exome-wide mutation profile in benzo[a]pyrene-derived post-stasis and immortal human mammary epithelial cells. Mutat Res Genet Toxicol Environ Mutagen. 2014 Dec;775-776:48-54. doi: 10.1016/j.mrgentox.2014.10.011. Epub 2014 Nov 4.
3 Human Adenine Nucleotide Translocase (ANT) Modulators Identified by High-Throughput Screening of Transgenic Yeast. J Biomol Screen. 2016 Apr;21(4):381-90. doi: 10.1177/1087057115624637. Epub 2016 Jan 8.