Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT2NHE5E)

• DOT Name: Pyruvate dehydrogenase E1 component subunit beta, mitochondrial (PDHB)
• Synonyms: PDHE1-B; EC 1.2.4.1
• Gene Name: PDHB
• Related Disease:
  Breast cancer
  Breast carcinoma
  Clear cell renal carcinoma
  Myocardial infarction
  Non-insulin dependent diabetes
  Papillary renal cell carcinoma
  Pyruvate dehydrogenase complex deficiency
  Pyruvate dehydrogenase E1-beta deficiency
  Renal cell carcinoma
  Leigh syndrome
  Melanoma
• UniProt ID: ODPB_HUMAN
• PDB ID: 1NI4; 2OZL; 3EXE; 3EXF; 3EXG; 3EXH; 3EXI; 6CER; 6CFO
• EC Number: 1.2.4.1
• Pfam ID: PF02779 ; PF02780
• Sequence:
  MAAVSGLVRRPLREVSGLLKRRFHWTAPAALQVTVRDAINQGMDEELERDEKVFLLGEEV
  AQYDGAYKVSRGLWKKYGDKRIIDTPISEMGFAGIAVGAAMAGLRPICEFMTFNFSMQAI
  DQVINSAAKTYYMSGGLQPVPIVFRGPNGASAGVAAQHSQCFAAWYGHCPGLKVVSPWNS
  EDAKGLIKSAIRDNNPVVVLENELMYGVPFEFPPEAQSKDFLIPIGKAKIERQGTHITVV
  SHSRPVGHCLEAAAVLSKEGVECEVINMRTIRPMDMETIEASVMKTNHLVTVEGGWPQFG
  VGAEICARIMEGPAFNFLDAPAVRVTGADVPMPYAKILEDNSIPQVKDIIFAIKKTLNI
• Function: The pyruvate dehydrogenase complex catalyzes the overall conversion of pyruvate to acetyl-CoA and CO(2), and thereby links the glycolytic pathway to the tricarboxylic cycle.
• KEGG Pathway:
  Glycolysis / Gluconeogenesis (hsa00010)
  Citrate cycle (TCA cycle) (hsa00020)
  Pyruvate metabolism (hsa00620)
  Lipoic acid metabolism (hsa00785)
  Metabolic pathways (hsa01100)
  Carbon metabolism (hsa01200)
  2-Oxocarboxylic acid metabolism (hsa01210)
  HIF-1 sig.ling pathway (hsa04066)
  Glucagon sig.ling pathway (hsa04922)
  Central carbon metabolism in cancer (hsa05230)
  Diabetic cardiomyopathy (hsa05415)
• Reactome Pathway:
  Glyoxylate metabolism and glycine degradation (R-HSA-389661)
  Signaling by Retinoic Acid (R-HSA-5362517)
  Pyruvate metabolism (R-HSA-70268)
  Regulation of pyruvate dehydrogenase (PDH) complex (R-HSA-204174)
• BioCyc Pathway: MetaCyc:HS09727-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
Breast cancer	DIS7DPX1	Strong	Biomarker	[1]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[1]
Clear cell renal carcinoma	DISBXRFJ	Strong	Biomarker	[2]
Myocardial infarction	DIS655KI	Strong	Biomarker	[3]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Altered Expression	[4]
Papillary renal cell carcinoma	DIS25HBV	Strong	Biomarker	[2]
Pyruvate dehydrogenase complex deficiency	DIS8RZP9	Strong	Genetic Variation	[5]
Pyruvate dehydrogenase E1-beta deficiency	DISF8VD1	Strong	Autosomal recessive	[6]
Renal cell carcinoma	DISQZ2X8	Strong	Biomarker	[2]
Leigh syndrome	DISWQU45	Moderate	Autosomal recessive	[7]
Melanoma	DIS1RRCY	Limited	Biomarker	[8]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Vinblastine	DM5TVS3	Approved	Pyruvate dehydrogenase E1 component subunit beta, mitochondrial (PDHB) affects the response to substance of Vinblastine.	[21]

11 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 Pyruvate dehydrogenase E1 component subunit beta, mitochondrial (PDHB).	[9]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Pyruvate dehydrogenase E1 component subunit beta, mitochondrial (PDHB).	[10]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Pyruvate dehydrogenase E1 component subunit beta, mitochondrial (PDHB).	[11]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Pyruvate dehydrogenase E1 component subunit beta, mitochondrial (PDHB).	[12]
Marinol	DM70IK5	Approved	Marinol increases the expression of Pyruvate dehydrogenase E1 component subunit beta, mitochondrial (PDHB).	[13]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Pyruvate dehydrogenase E1 component subunit beta, mitochondrial (PDHB).	[14]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of Pyruvate dehydrogenase E1 component subunit beta, mitochondrial (PDHB).	[15]
Imatinib	DM7RJXL	Approved	Imatinib decreases the expression of Pyruvate dehydrogenase E1 component subunit beta, mitochondrial (PDHB).	[16]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of Pyruvate dehydrogenase E1 component subunit beta, mitochondrial (PDHB).	[18]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Pyruvate dehydrogenase E1 component subunit beta, mitochondrial (PDHB).	[19]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Pyruvate dehydrogenase E1 component subunit beta, mitochondrial (PDHB).	[20]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
DNCB	DMDTVYC	Phase 2	DNCB affects the binding of Pyruvate dehydrogenase E1 component subunit beta, mitochondrial (PDHB).	[17]

References

• [1] Gene expression profile and cancer-associated pathways linked to progesterone receptor isoform a (PRA) predominance in transgenic mouse mammary glands.BMC Cancer. 2018 Jun 25;18(1):682. doi: 10.1186/s12885-018-4550-z.
• [2] Spectrum of diverse genomic alterations define non-clear cell renal carcinoma subtypes.Nat Genet. 2015 Jan;47(1):13-21. doi: 10.1038/ng.3146. Epub 2014 Nov 17.
• [3] Modulation of NFKB1/p50 by ROS leads to impaired ATP production during MI compared to cardiac hypertrophy.J Cell Biochem. 2018 Feb;119(2):1575-1590. doi: 10.1002/jcb.26318. Epub 2017 Sep 12.
• [4] The expression of genes involved in jejunal lipogenesis and lipoprotein synthesis is altered in morbidly obese subjects with insulin resistance.Lab Invest. 2015 Dec;95(12):1409-17. doi: 10.1038/labinvest.2015.115. Epub 2015 Sep 14.
• [5] Pyruvate dehydrogenase complex deficiency caused by ubiquitination and proteasome-mediated degradation of the E1 subunit.J Biol Chem. 2008 Jan 4;283(1):237-243. doi: 10.1074/jbc.M704748200. Epub 2007 Oct 8.
• [6] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [7] 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.
• [8] MiR-370 functions as oncogene in melanoma by direct targeting pyruvate dehydrogenase B.Biomed Pharmacother. 2017 Jun;90:278-286. doi: 10.1016/j.biopha.2017.03.068. Epub 2017 Mar 30.
• [9] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [10] 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.
• [11] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [12] 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.
• [13] Single-cell Transcriptome Mapping Identifies Common and Cell-type Specific Genes Affected by Acute Delta9-tetrahydrocannabinol in Humans. Sci Rep. 2020 Feb 26;10(1):3450. doi: 10.1038/s41598-020-59827-1.
• [14] Zoledronate dysregulates fatty acid metabolism in renal tubular epithelial cells to induce nephrotoxicity. Arch Toxicol. 2018 Jan;92(1):469-485.
• [15] Temporal changes in gene expression in the skin of patients treated with isotretinoin provide insight into its mechanism of action. Dermatoendocrinol. 2009 May;1(3):177-87.
• [16] A systems biology understanding of the synergistic effects of arsenic sulfide and Imatinib in BCR/ABL-associated leukemia. Proc Natl Acad Sci U S A. 2009 Mar 3;106(9):3378-83.
• [17] Proteomic analysis of the cellular response to a potent sensitiser unveils the dynamics of haptenation in living cells. Toxicology. 2020 Dec 1;445:152603. doi: 10.1016/j.tox.2020.152603. Epub 2020 Sep 28.
• [18] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [19] 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.
• [20] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [21] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.