Molecule Information

General Information of the Molecule (ID: Mol04003)

• Name: Pyruvate dehydrogenase kinase 4 (PDK4) ,Rattus norvegicus
• Synonyms: Pyruvate dehydrogenase kinase isoform 4
• Molecule Type: Protein
• Gene Name: Pdk4
• Gene ID: 89813
• Sequence:
  MKAARFVMRSASSLGNAGLVPREVELFSRYSPSPLSMKQLLDFGSENACERTSFSFLRQE
  LPVRLANILKEIDILPEHLVNTPSVQLVKSWYIQSLMDLVEFHEKSPEDQKVLSDFVDTL
  VKVRNRHHNVVPTMAQGILEYKDNCTVDPVTNQNLQYFLDRFYMNRISTRMLMNQHILIF
  SDSKTGNPSHIGSIDPNCDVVAVVEDAFECAKMLCDQYYLTSPELKLTQVNGKFPGQPIH
  IVYVPSHLHHMLFELFKNAMRATVEHQENRPFLTPVEATVVLGKEDLTIKISDRGGGVPL
  RITDRLFSYTYSTAPTPVMDNSRNAPLAGFGYGLPISRLYAKYFQGDLNLYSMSGYGTDA
  IIYLKALSSESIEKLPVFNKSAFKHYQMSSEADDWCIPSKEPKNLSKEKLAV
• Function: Kinase that plays a key role in regulation of glucose and fatty acid metabolism and homeostasis via phosphorylation of the pyruvate dehydrogenase subunits PDHA1 and PDHA2. This inhibits pyruvate dehydrogenase activity, and thereby regulates metabolite flux through the tricarboxylic acid cycle, down-regulates aerobic respiration and inhibits the formation of acetyl-coenzyme A from pyruvate. Inhibition of pyruvate dehydrogenase decreases glucose utilization and increases fat metabolism in response to prolonged fasting and starvation. Plays an important role in maintaining normal blood glucose levels under starvation, and is involved in the insulin signaling cascade. Via its regulation of pyruvate dehydrogenase activity, plays an important role in maintaining normal blood pH and in preventing the accumulation of ketone bodies under starvation. In the fed state, mediates cellular responses to glucose levels and to a high-fat diet. Regulates both fatty acid oxidation and de novo fatty acid biosynthesis. Plays a role in the generation of reactive oxygen species. Protects detached epithelial cells against anoikis. Plays a role in cell proliferation via its role in regulating carbohydrate and fatty acid metabolism. .
• Uniprot ID: PDK4_RAT

Kingdom: Metazoa
Phylum: Chordata
Class: Mammalia
Order: Rodentia
Family: Muridae
Genus: Rattus
Species: Rattus norvegicus

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

Rituximab

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Metabolic Reprogramming via Altered Pathways (MRAP)

Disease Class: Diffuse large B-cell lymphoma [ICD-11: 2A81.0] [1]

• Metabolic Type: Glucose metabolism
• Resistant Disease: Diffuse large B-cell lymphoma [ICD-11: 2A81.0]
• Resistant Drug: Rituximab
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vivo Model: Female B-NDG mice (5-7 weeks old) , with PDK4-overexpressing OCI-ly8 cells; Mice
• Experiment for Molecule Alteration: qRT-PCR; Western blot analysis
• Experiment for Drug Resistance: Cell viability assay
• Mechanism Description: We found that overexpression of PDK4 in DLBCL cells resulted in cell proliferation and resistance to rituximab in vitro and in vivo. Furthermore, loss of PDK4 expression or treatment with the PDK4 inhibitor dichloroacetate was able to significantly increase rituximab-induced cell apoptosis in DLBCL cells. Further studies suggested PDK4 mediates a metabolic shift, in that the main energy source was changed from oxidative phosphorylation to glycolysis, and the metabolic changes could play an important role in rituximab resistance. Importantly, by knocking down or overexpressing PDK4 in DLBCL cells, we showed that PDK4 has a negative regulation effect on MS4A1/CD20 expression

References

• Ref 1: Pyruvate dehydrogenase kinase 4-mediated metabolic reprogramming is involved in rituximab resistance in diffuse large B-cell lymphoma by affecting the expression of MS4A1/CD20. Cancer Sci. 2021 Sep;112(9):3585-3597.