PDK4
Description
The PDK4 (pyruvate dehydrogenase kinase 4) is a protein-coding gene located on chromosome 7.
PDK4, also known as Pyruvate dehydrogenase kinase isoform 4, is a mitochondrial enzyme encoded by the PDK4 gene in humans. It is a member of the PDK/BCKDK protein kinase family and contains a histidine kinase domain. PDK4 is located in the mitochondrial matrix and inhibits the pyruvate dehydrogenase complex by phosphorylating one of its subunits, reducing the conversion of pyruvate to acetyl-CoA and regulating glucose metabolism. Its expression is influenced by glucocorticoids, retinoic acid, and insulin. During hibernation, PDK4 levels increase, helping to decrease metabolism and conserve glucose by inhibiting its conversion to acetyl-CoA, which enters the citric acid cycle and is converted to ATP. The mature PDK4 protein contains 294 amino acids and forms an active protein by dimerizing, with two polypeptide chains forming an open conformation and creating a nucleotide-binding pocket that is often targeted by inhibitors. The pyruvate dehydrogenase complex, a central player in metabolism, is tightly regulated. Phosphorylation of three serine residues on the E1 component of the complex inactivates it.
PDK4 is a kinase that plays a crucial role in regulating glucose and fatty acid metabolism, primarily by phosphorylating the PDHA1 and PDHA2 subunits of the pyruvate dehydrogenase complex. This phosphorylation inhibits the complex's activity, influencing the flow of metabolites through the citric acid cycle, reducing aerobic respiration, and hindering the conversion of pyruvate to acetyl-CoA. Under prolonged fasting or starvation, PDK4's inhibition of pyruvate dehydrogenase decreases glucose utilization and promotes fat metabolism. PDK4 is essential for maintaining normal blood glucose levels during starvation and is involved in the insulin signaling pathway. By controlling pyruvate dehydrogenase activity, PDK4 contributes to maintaining normal blood pH and preventing the buildup of ketone bodies during starvation. In a well-nourished state, PDK4 mediates cellular responses to glucose levels and high-fat diets, influencing both fatty acid oxidation and de novo fatty acid biosynthesis. It also participates in the production of reactive oxygen species, protects detached epithelial cells from anoikis (programmed cell death), and plays a role in cell proliferation through its regulation of carbohydrate and fatty acid metabolism.
PDK4 is also known as -.
