Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTA556MK)

• DOT Name: Dicarboxylate carrier SLC25A8
• Synonyms: Mitochondrial uncoupling protein 2; UCP 2; Solute carrier family 25 member 8; UCPH
• Gene Name: UCP2
• Related Disease: Hyperinsulinism due to UCP2 deficiency
• UniProt ID: UCP2_HUMAN
• Pfam ID: PF00153
• Sequence:
  MVGFKATDVPPTATVKFLGAGTAACIADLITFPLDTAKVRLQIQGESQGPVRATASAQYR
  GVMGTILTMVRTEGPRSLYNGLVAGLQRQMSFASVRIGLYDSVKQFYTKGSEHASIGSRL
  LAGSTTGALAVAVAQPTDVVKVRFQAQARAGGGRRYQSTVNAYKTIAREEGFRGLWKGTS
  PNVARNAIVNCAELVTYDLIKDALLKANLMTDDLPCHFTSAFGAGFCTTVIASPVDVVKT
  RYMNSALGQYSSAGHCALTMLQKEGPRAFYKGFMPSFLRLGSWNVVMFVTYEQLKRALMA
  ACTSREAPF
• Function: Antiporter that exports dicarboxylate intermediates of the Krebs cycle in exchange for phosphate plus a proton across the inner membrane of mitochondria, a process driven by mitochondrial motive force with an overall impact on glycolysis, glutaminolysis and glutathione-dependent redox balance. Continuous export of oxaloacetate and related four-carbon dicarboxylates from mitochondrial matrix into the cytosol negatively regulates the oxidation of acetyl-CoA substrates via the Krebs cycle, lowering the ATP/ADP ratio and reactive oxygen species (ROS) production. Proton transporter activity is debated, but if it occurs it may mediate inducible proton re-entry into the mitochondrial matrix affecting ATP turnover as a protection mechanism against oxidative stress. Proton re-entry may be coupled to metabolite transport to allow for proton flux switching and optimal ATP turnover. Regulates the use of glucose as a source of energy. Required for glucose-induced DRP1-dependent mitochondrial fission and neuron activation in the ventromedial nucleus of the hypothalamus (VMH). This mitochondrial adaptation mechanism modulates the VMH pool of glucose-excited neurons with an impact on systemic glucose homeostasis. Regulates ROS levels and metabolic reprogramming of macrophages during the resolution phase of inflammation. Attenuates ROS production in response to IL33 to preserve the integrity of the Krebs cycle required for persistent production of itaconate and subsequent GATA3-dependent differentiation of inflammation-resolving alternatively activated macrophages. Can unidirectionally transport anions including L-malate, L-aspartate, phosphate and chloride ions. Does not mediate adaptive thermogenesis.
• Tissue Specificity: Widely expressed in adult human tissues, including tissues rich in macrophages. Most expressed in white adipose tissue and skeletal muscle.
• Reactome Pathway:
  The proton buffering model (R-HSA-167827)
  The fatty acid cycling model (R-HSA-167826)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hyperinsulinism due to UCP2 deficiency	DIS9LK5R	Supportive	Autosomal dominant	[1]

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Capsaicin	DMGMF6V	Approved	Dicarboxylate carrier SLC25A8 affects the response to substance of Capsaicin.	[30]
Paraquat	DMR8O3X	Investigative	Dicarboxylate carrier SLC25A8 decreases the response to substance of Paraquat.	[32]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ergotidine	DM78IME	Approved	Dicarboxylate carrier SLC25A8 decreases the secretion of Ergotidine.	[31]

28 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 Dicarboxylate carrier SLC25A8.	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Dicarboxylate carrier SLC25A8.	[3]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Dicarboxylate carrier SLC25A8.	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Dicarboxylate carrier SLC25A8.	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Dicarboxylate carrier SLC25A8.	[6]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Dicarboxylate carrier SLC25A8.	[7]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Dicarboxylate carrier SLC25A8.	[8]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Dicarboxylate carrier SLC25A8.	[9]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Dicarboxylate carrier SLC25A8.	[10]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Dicarboxylate carrier SLC25A8.	[11]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Dicarboxylate carrier SLC25A8.	[12]
Marinol	DM70IK5	Approved	Marinol increases the expression of Dicarboxylate carrier SLC25A8.	[13]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Dicarboxylate carrier SLC25A8.	[14]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil decreases the expression of Dicarboxylate carrier SLC25A8.	[15]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of Dicarboxylate carrier SLC25A8.	[16]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone increases the expression of Dicarboxylate carrier SLC25A8.	[17]
Etoposide	DMNH3PG	Approved	Etoposide decreases the expression of Dicarboxylate carrier SLC25A8.	[18]
Indomethacin	DMSC4A7	Approved	Indomethacin increases the expression of Dicarboxylate carrier SLC25A8.	[19]
Fenofibrate	DMFKXDY	Approved	Fenofibrate increases the expression of Dicarboxylate carrier SLC25A8.	[20]
Stavudine	DM6DEK9	Approved	Stavudine decreases the expression of Dicarboxylate carrier SLC25A8.	[21]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Dicarboxylate carrier SLC25A8.	[22]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Dicarboxylate carrier SLC25A8.	[24]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of Dicarboxylate carrier SLC25A8.	[25]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Dicarboxylate carrier SLC25A8.	[26]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A decreases the expression of Dicarboxylate carrier SLC25A8.	[27]
Hexadecanoic acid	DMWUXDZ	Investigative	Hexadecanoic acid increases the activity of Dicarboxylate carrier SLC25A8.	[28]
D-glucose	DMMG2TO	Investigative	D-glucose increases the expression of Dicarboxylate carrier SLC25A8.	[29]
Linalool	DMGZQ5P	Investigative	Linalool increases the expression of Dicarboxylate carrier SLC25A8.	[20]

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 decreases the methylation of Dicarboxylate carrier SLC25A8.	[23]

References

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