Details of Drug Off-Target (DOT)

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

• DOT Name: 2-oxoadipate dehydrogenase complex component E1 (DHTKD1)
• Synonyms: E1a; OADC-E1; OADH-E1; EC 1.2.4.-; 2-oxoadipate dehydrogenase, mitochondrial; Alpha-ketoadipate dehydrogenase; Alpha-KADH-E1; Dehydrogenase E1 and transketolase domain-containing protein 1; Probable 2-oxoglutarate dehydrogenase E1 component DHKTD1, mitochondrial
• Gene Name: DHTKD1
• Related Disease:
  2-aminoadipic 2-oxoadipic aciduria
  Charcot marie tooth disease
  Charcot-Marie-Tooth disease axonal type 2Q
  Charcot-Marie-Tooth disease type 2
  Eosinophilic esophagitis
  Postmenopausal osteoporosis
  Charcot-Marie-Tooth disease type 3
  Esophageal disorder
  Glutaryl-CoA dehydrogenase deficiency
  Hereditary motor and sensory neuropathy
  Metabolic disorder
• UniProt ID: DHTK1_HUMAN
• PDB ID: 5RVW; 5RVX; 5RVY; 5RVZ; 5RW0; 5RW1; 6SY1; 6U3J
• EC Number: 1.2.4.-
• Pfam ID: PF00676 ; PF16870 ; PF02779
• Sequence:
  MASATAAAARRGLGRALPLFWRGYQTERGVYGYRPRKPESREPQGALERPPVDHGLARLV
  TVYCEHGHKAAKINPLFTGQALLENVPEIQALVQTLQGPFHTAGLLNMGKEEASLEEVLV
  YLNQIYCGQISIETSQLQSQDEKDWFAKRFEELQKETFTTEERKHLSKLMLESQEFDHFL
  ATKFSTVKRYGGEGAESMMGFFHELLKMSAYSGITDVIIGMPHRGRLNLLTGLLQFPPEL
  MFRKMRGLSEFPENFSATGDVLSHLTSSVDLYFGAHHPLHVTMLPNPSHLEAVNPVAVGK
  TRGRQQSRQDGDYSPDNSAQPGDRVICLQVHGDASFCGQGIVPETFTLSNLPHFRIGGSV
  HLIVNNQLGYTTPAERGRSSLYCSDIGKLVGCAIIHVNGDSPEEVVRATRLAFEYQRQFR
  KDVIIDLLCYRQWGHNELDEPFYTNPIMYKIIRARKSIPDTYAEHLIAGGLMTQEEVSEI
  KSSYYAKLNDHLNNMAHYRPPALNLQAHWQGLAQPEAQITTWSTGVPLDLLRFVGMKSVE
  VPRELQMHSHLLKTHVQSRMEKMMDGIKLDWATAEALALGSLLAQGFNVRLSGQDVGRGT
  FSQRHAIVVCQETDDTYIPLNHMDPNQKGFLEVSNSPLSEEAVLGFEYGMSIESPKLLPL
  WEAQFGDFFNGAQIIFDTFISGGEAKWLLQSGIVILLPHGYDGAGPDHSSCRIERFLQMC
  DSAEEGVDGDTVNMFVVHPTTPAQYFHLLRRQMVRNFRKPLIVASPKMLLRLPAAVSTLQ
  EMAPGTTFNPVIGDSSVDPKKVKTLVFCSGKHFYSLVKQRESLGAKKHDFAIIRVEELCP
  FPLDSLQQEMSKYKHVKDHIWSQEEPQNMGPWSFVSPRFEKQLACKLRLVGRPPLPVPAV
  GIGTVHLHQHEDILAKTFA
• Function: 2-oxoadipate dehydrogenase (E1a) component of the 2-oxoadipate dehydrogenase complex (OADHC). Participates in the first step, rate limiting for the overall conversion of 2-oxoadipate (alpha-ketoadipate) to glutaryl-CoA and CO(2) catalyzed by the whole OADHC. Catalyzes the irreversible decarboxylation of 2-oxoadipate via the thiamine diphosphate (ThDP) cofactor and subsequent transfer of the decarboxylated acyl intermediate on an oxidized dihydrolipoyl group that is covalently amidated to the E2 enzyme (dihydrolipoyllysine-residue succinyltransferase or DLST) (Probable). Can catalyze the decarboxylation of 2-oxoglutarate in vitro, but at a much lower rate than 2-oxoadipate. Responsible for the last step of L-lysine, L-hydroxylysine and L-tryptophan catabolism with the common product being 2-oxoadipate (Probable).
• KEGG Pathway:
  Lysine degradation (hsa00310)
  Tryptophan metabolism (hsa00380)
  Lipoic acid metabolism (hsa00785)
  Metabolic pathways (hsa01100)
  2-Oxocarboxylic acid metabolism (hsa01210)
• Reactome Pathway: Glyoxylate metabolism and glycine degradation (R-HSA-389661)
• BioCyc Pathway: MetaCyc:HS11585-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

11 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
2-aminoadipic 2-oxoadipic aciduria	DISN0NX1	Definitive	Autosomal recessive	[1]
Charcot marie tooth disease	DIS3BT2L	Strong	Genetic Variation	[2]
Charcot-Marie-Tooth disease axonal type 2Q	DISM66KB	Strong	Autosomal dominant	[3]
Charcot-Marie-Tooth disease type 2	DISR30O9	Strong	Genetic Variation	[3]
Eosinophilic esophagitis	DISR8WSB	Strong	Genetic Variation	[4]
Postmenopausal osteoporosis	DISS0RQZ	Strong	Biomarker	[5]
Charcot-Marie-Tooth disease type 3	DIS6DQK1	Limited	Biomarker	[6]
Esophageal disorder	DIS5L3HQ	Limited	Genetic Variation	[4]
Glutaryl-CoA dehydrogenase deficiency	DISRAMPH	Limited	Biomarker	[7]
Hereditary motor and sensory neuropathy	DISR0X2K	Limited	Biomarker	[6]
Metabolic disorder	DIS71G5H	Limited	Genetic Variation	[4]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of 2-oxoadipate dehydrogenase complex component E1 (DHTKD1).	[8]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of 2-oxoadipate dehydrogenase complex component E1 (DHTKD1).	[9]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of 2-oxoadipate dehydrogenase complex component E1 (DHTKD1).	[10]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of 2-oxoadipate dehydrogenase complex component E1 (DHTKD1).	[11]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of 2-oxoadipate dehydrogenase complex component E1 (DHTKD1).	[12]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of 2-oxoadipate dehydrogenase complex component E1 (DHTKD1).	[13]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of 2-oxoadipate dehydrogenase complex component E1 (DHTKD1).	[14]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of 2-oxoadipate dehydrogenase complex component E1 (DHTKD1).	[15]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of 2-oxoadipate dehydrogenase complex component E1 (DHTKD1).	[16]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of 2-oxoadipate dehydrogenase complex component E1 (DHTKD1).	[17]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of 2-oxoadipate dehydrogenase complex component E1 (DHTKD1).	[18]

References

• [1] 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.
• [2] A Chinese pedigree with a novel mutation in GJB1 gene and a rare variation in DHTKD1 gene for diverse CharcotMarieTooth diseases.Mol Med Rep. 2019 May;19(5):4484-4490. doi: 10.3892/mmr.2019.10058. Epub 2019 Mar 19.
• [3] A nonsense mutation in DHTKD1 causes Charcot-Marie-Tooth disease type 2 in a large Chinese pedigree. Am J Hum Genet. 2012 Dec 7;91(6):1088-94. doi: 10.1016/j.ajhg.2012.09.018. Epub 2012 Nov 8.
• [4] Human 2-Oxoglutarate Dehydrogenase and 2-Oxoadipate Dehydrogenase Both Generate Superoxide/H(2)O(2) in a Side Reaction and Each Could Contribute to Oxidative Stress in Mitochondria.Neurochem Res. 2019 Oct;44(10):2325-2335. doi: 10.1007/s11064-019-02765-w. Epub 2019 Mar 7.
• [5] Identification of gene biomarkers in patients with postmenopausal osteoporosis.Mol Med Rep. 2019 Feb;19(2):1065-1073. doi: 10.3892/mmr.2018.9752. Epub 2018 Dec 12.
• [6] DHTKD1 Deficiency Causes Charcot-Marie-Tooth Disease in Mice.Mol Cell Biol. 2018 Jun 14;38(13):e00085-18. doi: 10.1128/MCB.00085-18. Print 2018 Jul 1.
• [7] Elevated glutaric acid levels in Dhtkd1-/Gcdh- double knockout mice challenge our current understanding of lysine metabolism.Biochim Biophys Acta Mol Basis Dis. 2017 Sep;1863(9):2220-2228. doi: 10.1016/j.bbadis.2017.05.018. Epub 2017 May 22.
• [8] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [9] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [10] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [11] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [12] 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.
• [13] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [14] Proteomics-based identification of differentially abundant proteins from human keratinocytes exposed to arsenic trioxide. J Proteomics Bioinform. 2014 Jul;7(7):166-178.
• [15] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [16] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [17] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [18] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.