Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT8J2PD8)

• DOT Name: Hydroxyacid-oxoacid transhydrogenase, mitochondrial (ADHFE1)
• Synonyms: HOT; EC 1.1.99.24; Alcohol dehydrogenase iron-containing protein 1; ADHFe1; Fe-containing alcohol dehydrogenase
• Gene Name: ADHFE1
• UniProt ID: HOT_HUMAN
• EC Number: 1.1.99.24
• Pfam ID: PF00465
• Sequence:
  MAAAARARVAYLLRQLQRAACQCPTHSHTYSQAPGLSPSGKTTDYAFEMAVSNIRYGAAV
  TKEVGMDLKNMGAKNVCLMTDKNLSKLPPVQVAMDSLVKNGIPFTVYDNVRVEPTDSSFM
  EAIEFAQKGAFDAYVAVGGGSTMDTCKAANLYASSPHSDFLDYVSAPIGKGKPVSVPLKP
  LIAVPTTSGTGSETTGVAIFDYEHLKVKIGITSRAIKPTLGLIDPLHTLHMPARVVANSG
  FDVLCHALESYTTLPYHLRSPCPSNPITRPAYQGSNPISDIWAIHALRIVAKYLKRAVRN
  PDDLEARSHMHLASAFAGIGFGNAGVHLCHGMSYPISGLVKMYKAKDYNVDHPLVPHGLS
  VVLTSPAVFTFTAQMFPERHLEMAEILGADTRTARIQDAGLVLADTLRKFLFDLDVDDGL
  AAVGYSKADIPALVKGTLPQERVTKLAPCPQSEEDLAALFEASMKLY
• Function: Catalyzes the cofactor-independent reversible oxidation of gamma-hydroxybutyrate (GHB) to succinic semialdehyde (SSA) coupled to reduction of 2-ketoglutarate (2-KG) to D-2-hydroxyglutarate (D-2-HG). D,L-3-hydroxyisobutyrate and L-3-hydroxybutyrate (L-3-OHB) are also substrates for HOT with 10-fold lower activities.
• Tissue Specificity: Only expressed in adult liver.
• Reactome Pathway: Interconversion of 2-oxoglutarate and 2-hydroxyglutarate (R-HSA-880009)

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Hydroxyacid-oxoacid transhydrogenase, mitochondrial (ADHFE1).	[1]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Hydroxyacid-oxoacid transhydrogenase, mitochondrial (ADHFE1).	[2]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Hydroxyacid-oxoacid transhydrogenase, mitochondrial (ADHFE1).	[3]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Hydroxyacid-oxoacid transhydrogenase, mitochondrial (ADHFE1).	[4]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Hydroxyacid-oxoacid transhydrogenase, mitochondrial (ADHFE1).	[5]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of Hydroxyacid-oxoacid transhydrogenase, mitochondrial (ADHFE1).	[7]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Hydroxyacid-oxoacid transhydrogenase, mitochondrial (ADHFE1).	[8]

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 Hydroxyacid-oxoacid transhydrogenase, mitochondrial (ADHFE1).	[6]

References

• [1] 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.
• [2] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [3] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [4] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [5] 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.
• [6] 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.
• [7] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [8] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.