PDK3
Description
The PDK3 (pyruvate dehydrogenase kinase 3) is a protein-coding gene located on chromosome X.
PDK3, also known as Pyruvate dehydrogenase lipoamide kinase isozyme 3, mitochondrial, is an enzyme encoded by the PDK3 gene in humans. It is an isozyme of pyruvate dehydrogenase kinase. The pyruvate dehydrogenase (PDH) complex is a nuclear-encoded mitochondrial multienzyme complex that catalyzes the conversion of pyruvate to acetyl-CoA and CO2. It links glycolysis to the tricarboxylic acid (TCA) cycle, making it a crucial enzyme in regulating glucose metabolism. PDH activity is regulated by phosphorylation/dephosphorylation. Phosphorylation inactivates PDH. PDK3 is one of four pyruvate dehydrogenase kinases that inhibit the PDH complex by phosphorylating the E1 alpha subunit. PDK3 is primarily expressed in the heart and skeletal muscles. Alternative splicing generates different isoforms of the gene. When the L2 domain binds to PDK3, it induces a "cross-tail" conformation in PDK3, thereby stimulating activity. Three crucial residues, Leu-140, Glu-170, and Glu-179, in the C-terminal domain are essential for this interaction. Structural studies suggest that L2 binding stimulates activity by disrupting the closed conformation, or ATP lid, to remove product inhibition.
PDK3 inhibits pyruvate dehydrogenase activity by phosphorylating the E1 subunit PDHA1, regulating glucose metabolism and aerobic respiration. It can also phosphorylate PDHA2. PDK3 decreases glucose utilization and increases fat metabolism during prolonged fasting or adaptation to a high-fat diet. It contributes to glucose homeostasis and maintaining normal blood glucose levels in response to nutrient levels and starvation. PDK3 plays a role in the generation of reactive oxygen species.
PDK3 is also known as CMTX6, GS1-358P8.4.
