What role does pyruvate dehydrogenase play in metabolism?
One of the major enzymes responsible for metabolic flexibility in mammals is the pyruvate dehydrogenase complex (PDC), a mitochondrial multi-enzyme complex that catalyzes the oxidative decarboxylation of pyruvate [5]. Thus, the PDC occupies a central position in cellular energy metabolism (Figure 1).
How does pyruvate dehydrogenase complex work?
The pyruvate dehydrogenase complex catalyzes, through five sequential reactions, the oxidative decarboxylation of pyruvate, an α-keto acid, to form a carbon dioxide molecules (CO2) and the acetyl group of acetyl-coenzyme A or acetyl-CoA, with the release of two electrons, carried by NAD.
How is pyruvate dehydrogenase activity inhibited during high rate of fatty acid oxidation?
PDH can be inhibited by phosphorylation of 3 serine residues on the E1α subunit. Reflective of reduced enzyme activity, phosphorylation of PDH was elevated during states 2 and 3 respiration in mitochondria isolated from mice fed a high fat relative to control diet (Figure 2D and E).
What are the 3 functions of pyruvate dehydrogenase?
Pyruvate Dehydrogenase complex (PDH) connects the citric acid cycle and subsquent oxidative phosphorylation to the glycolysis, gluconeogenesis and lipid and amino acid metabolism pathways.
What occurs in pyruvate oxidation?
Pyruvate is produced by glycolysis in the cytoplasm, but pyruvate oxidation takes place in the mitochondrial matrix (in eukaryotes). A carboxyl group is removed from pyruvate and released as carbon dioxide. The two-carbon molecule from the first step is oxidized, and NAD+ accepts the electrons to form NADH.
What is pyruvate dehydrogenase activated by?
Pyruvate dehydrogenase kinase is activated by ATP, NADH and acetyl-CoA. It is inhibited by ADP, NAD+, CoA-SH and pyruvate. Each isozyme responds to each of these factors slightly differently. NADH stimulates PDK1 activity by 20% and PDK2 activity by 30%.
What is the name of the mechanism by which pyruvate dehydrogenase is inhibited by the end product of the biochemical pathway?
The mechanisms that control PDC activity include end product inhibition by increased mitochondrial acetyl-CoA, NADH and ATP concentrations (which can also be generated by FA oxidation) and post-translational modification, namely its phosphorylation (inactivation) by a family of pyruvate dehydrogenase kinases (PDHKs 1–4 …
What activates the pyruvate dehydrogenase complex?
PDH kinase is stimulated by NADH and acetyl-CoA. It is inhibited by pyruvate. PDH phosphatase is stimulated by Ca++ and insulin.
What happens if pyruvate dehydrogenase is inhibited?
Pyruvate dehydrogenase kinase 4 (PDK4) is a regulator of PDH, as it inhibits PDH activity, which in turn will increase the influx of acetyl-coA from beta-oxidation into the TCA cycle, thereby leading to enhanced FA oxidation and slowing of glycolysis or glycolytic intermediates to alternative metabolic pathways.
What is pyruvate dehydrogenase inhibited by?
Pyruvate dehydrogenase is inhibited when one or more of the three following ratios are increased: ATP/ADP, NADH/NAD+ and acetyl-CoA/CoA.
What happens when pyruvate oxidation is blocked?
If pyruvate oxidation is blocked, what will happen to the levels of oxaloacetate and citrate in the citric acid cycle shown in the figure? Oxaloacetate will accumulate and citrate will decrease. Under anaerobic conditions (a lack of oxygen), the conversion of pyruvate to acetyl CoA stops.