Molecule Information

General Information of the Molecule (ID: Mol04060)

• Name: Pyruvate dehydrogenase (PDH) ,Homo sapiens
• Synonyms: Pyruvate dehydrogenase kinase isoform 3
• Molecule Type: Protein
• Gene Name: PDK3
• Gene ID: 5165
• Location: chrX:24465244-24550466[+]
• Sequence:
  MRLFRWLLKQPVPKQIERYSRFSPSPLSIKQFLDFGRDNACEKTSYMFLRKELPVRLANT
  MREVNLLPDNLLNRPSVGLVQSWYMQSFLELLEYENKSPEDPQVLDNFLQVLIKVRNRHN
  DVVPTMAQGVIEYKEKFGFDPFISTNIQYFLDRFYTNRISFRMLINQHTLLFGGDTNPVH
  PKHIGSIDPTCNVADVVKDAYETAKMLCEQYYLVAPELEVEEFNAKAPDKPIQVVYVPSH
  LFHMLFELFKNSMRATVELYEDRKEGYPAVKTLVTLGKEDLSIKISDLGGGVPLRKIDRL
  FNYMYSTAPRPSLEPTRAAPLAGFGYGLPISRLYARYFQGDLKLYSMEGVGTDAVIYLKA
  LSSESFERLPVFNKSAWRHYKTTPEADDWSNPSSEPRDASKYKAKQ
• 3D-structure: PDB ID: 1Y8O; Classification: Transferase; Method: X-ray diffraction; Resolution: 2.48 Å
• Function: Inhibits pyruvate dehydrogenase activity by phosphorylation of the E1 subunit PDHA1, and thereby regulates glucose metabolism and aerobic respiration. Can also phosphorylate PDHA2. Decreases glucose utilization and increases fat metabolism in response to prolonged fasting, and as adaptation to a high-fat diet. Plays a role in glucose homeostasis and in maintaining normal blood glucose levels in function of nutrient levels and under starvation. Plays a role in the generation of reactive oxygen species. .
• Uniprot ID: PDK3_HUMAN
• Ensembl ID: ENSG00000067992
• HGNC ID: HGNC:8811

Kingdom: Metazoa
Phylum: Chordata
Class: Mammalia
Order: Primates
Family: Hominidae
Genus: Homo
Species: Homo sapiens

Type(s) of Resistant Mechanism of This Molecule

  MRAP: Metabolic Reprogramming via Altered Pathways

Drug Resistance Data Categorized by Drug

Approved Drug(s) 1 drug(s) in total

Doxorubicin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Metabolic Reprogramming via Altered Pathways (MRAP)

Disease Class: Mammary carcinoma [ICD-11: 2C61.1] [1]

• Metabolic Type: Glucose metabolism
• Resistant Disease: Mammary carcinoma [ICD-11: 2C61.1]
• Resistant Drug: Doxorubicin
• Molecule Alteration: Phosphorylation; tyrosine-289
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: 4T1 cells expressing WT; Breast; Mus musculus (Mouse); CVCL_0125
• In Vitro Model: 4T1 cells expressing Y289F PDHA1; Breast; Mus musculus (Mouse); CVCL_0125
• Experiment for Drug Resistance: Cell viability assay
• Mechanism Description: The results suggest that Src contributes to the Warburg phenotype by inactivating PDH through tyrosine phosphorylation, and the metabolic effect of Src is essential for Src-driven malignancy and therapy resistance. Combination therapies consisting of both Src inhibitors and pro-oxidants may improve anticancer efficacy.

Clinical Trial Drug(s) 1 drug(s) in total

Saracatinib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Metabolic Reprogramming via Altered Pathways (MRAP)

Disease Class: Pancreatic ductal adenocarcinoma [ICD-11: 2C10.0] [1]

• Metabolic Type: Glucose metabolism
• Resistant Disease: Pancreatic ductal adenocarcinoma [ICD-11: 2C10.0]
• Resistant Drug: Saracatinib
• Molecule Alteration: Phosphorylation; tyrosine-289
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: AsPC1 pancreatic cancer cells; Pancreas; Homo sapiens (Human); CVCL_0152
• Mechanism Description: The results suggest that Src contributes to the Warburg phenotype by inactivating PDH through tyrosine phosphorylation, and the metabolic effect of Src is essential for Src-driven malignancy and therapy resistance. Combination therapies consisting of both Src inhibitors and pro-oxidants may improve anticancer efficacy.

Disease Class: Mammary carcinoma [ICD-11: 2C61.1] [1]

• Metabolic Type: Glucose metabolism
• Resistant Disease: Mammary carcinoma [ICD-11: 2C61.1]
• Resistant Drug: Saracatinib
• Molecule Alteration: Phosphorylation; tyrosine-289
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: 4T1 mammary carcinoma cells; Breast; Mus musculus (Mouse); CVCL_0125
• Mechanism Description: The results suggest that Src contributes to the Warburg phenotype by inactivating PDH through tyrosine phosphorylation, and the metabolic effect of Src is essential for Src-driven malignancy and therapy resistance. Combination therapies consisting of both Src inhibitors and pro-oxidants may improve anticancer efficacy.

Disease Class: Human colon cancer [ICD-11: 2B90.0] [1]

• Metabolic Type: Glucose metabolism
• Resistant Disease: Human colon cancer [ICD-11: 2B90.0]
• Resistant Drug: Saracatinib
• Molecule Alteration: Phosphorylation; tyrosine-289
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: SW620 cells; Colon; Homo sapiens (Human); CVCL_0547
• Mechanism Description: The results suggest that Src contributes to the Warburg phenotype by inactivating PDH through tyrosine phosphorylation, and the metabolic effect of Src is essential for Src-driven malignancy and therapy resistance. Combination therapies consisting of both Src inhibitors and pro-oxidants may improve anticancer efficacy.

References

• Ref 1: Src drives the Warburg effect and therapy resistance by inactivating pyruvate dehydrogenase through tyrosine-289 phosphorylation. Oncotarget. 2016 May 3;7(18):25113-24.