Details of Drug Off-Target (DOT)

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

• DOT Name: Branched-chain alpha-ketoacid dehydrogenase kinase (BCKDK)
• Synonyms: BCKDH kinase; BCKDHKIN; BDK; EC 2.7.11.1; ] kinase, mitochondrial; EC 2.7.11.4
• Gene Name: BCKDK
• Related Disease: Branched-chain keto acid dehydrogenase kinase deficiency
• UniProt ID: BCKD_HUMAN
• PDB ID: 8F5F; 8F5J; 8F5S
• EC Number: 2.7.11.1; 2.7.11.4
• Pfam ID: PF10436 ; PF02518
• Sequence:
  MILASVLRSGPGGGLPLRPLLGPALALRARSTSATDTHHVEMARERSKTVTSFYNQSAID
  AAAEKPSVRLTPTMMLYAGRSQDGSHLLKSARYLQQELPVRIAHRIKGFRCLPFIIGCNP
  TILHVHELYIRAFQKLTDFPPIKDQADEAQYCQLVRQLLDDHKDVVTLLAEGLRESRKHI
  EDEKLVRYFLDKTLTSRLGIRMLATHHLALHEDKPDFVGIICTRLSPKKIIEKWVDFARR
  LCEHKYGNAPRVRINGHVAARFPFIPMPLDYILPELLKNAMRATMESHLDTPYNVPDVVI
  TIANNDVDLIIRISDRGGGIAHKDLDRVMDYHFTTAEASTQDPRISPLFGHLDMHSGAQS
  GPMHGFGFGLPTSRAYAEYLGGSLQLQSLQGIGTDVYLRLRHIDGREESFRI
• Function: Serine/threonine-protein kinase component of macronutrients metabolism. Forms a functional kinase and phosphatase pair with PPM1K, serving as a metabolic regulatory node that coordinates branched-chain amino acids (BCAAs) with glucose and lipid metabolism via two distinct phosphoprotein targets: mitochondrial BCKDHA subunit of the branched-chain alpha-ketoacid dehydrogenase (BCKDH) complex and cytosolic ACLY, a lipogenic enzyme of Krebs cycle. Phosphorylates and inactivates mitochondrial BCKDH complex a multisubunit complex consisting of three multimeric components each involved in different steps of BCAA catabolism: E1 composed of BCKDHA and BCKDHB, E2 core composed of DBT monomers, and E3 composed of DLD monomers. Associates with the E2 component of BCKDH complex and phosphorylates BCKDHA on Ser-337, leading to conformational changes that interrupt substrate channeling between E1 and E2 and inactivates the BCKDH complex. Phosphorylates ACLY on Ser-455 in response to changes in cellular carbohydrate abundance such as occurs during fasting to feeding metabolic transition. Refeeding stimulates MLXIPL/ChREBP transcription factor, leading to increased BCKDK to PPM1K expression ratio, phosphorylation and activation of ACLY that ultimately results in the generation of malonyl-CoA and oxaloacetate immediate substrates of de novo lipogenesis and glucogenesis, respectively. Recognizes phosphosites having SxxE/D canonical motif.
• Tissue Specificity: Ubiquitous.
• Reactome Pathway: Branched-chain amino acid catabolism (R-HSA-70895)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Branched-chain keto acid dehydrogenase kinase deficiency	DISRRUYP	Definitive	Autosomal recessive	[1]

3 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 Branched-chain alpha-ketoacid dehydrogenase kinase (BCKDK).	[2]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Branched-chain alpha-ketoacid dehydrogenase kinase (BCKDK).	[9]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Branched-chain alpha-ketoacid dehydrogenase kinase (BCKDK).	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Branched-chain alpha-ketoacid dehydrogenase kinase (BCKDK).	[3]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Branched-chain alpha-ketoacid dehydrogenase kinase (BCKDK).	[4]
Ivermectin	DMDBX5F	Approved	Ivermectin increases the expression of Branched-chain alpha-ketoacid dehydrogenase kinase (BCKDK).	[5]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Branched-chain alpha-ketoacid dehydrogenase kinase (BCKDK).	[6]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Branched-chain alpha-ketoacid dehydrogenase kinase (BCKDK).	[7]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Branched-chain alpha-ketoacid dehydrogenase kinase (BCKDK).	[8]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of Branched-chain alpha-ketoacid dehydrogenase kinase (BCKDK).	[11]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Branched-chain alpha-ketoacid dehydrogenase kinase (BCKDK).	[12]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Branched-chain alpha-ketoacid dehydrogenase kinase (BCKDK).	[13]

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] 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.
• [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] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [5] 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.
• [6] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [7] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [8] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [9] 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.
• [10] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [11] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [12] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [13] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.