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).
Why is it important to regulate PDHc?
The reactions of the PDHc serve to interconnect the metabolic pathways of glycolysis, gluconeogenesis and fatty acid oxidation to the TCA cycle. The activity of the PDHc is also important in regulating the flux from glucose to malonyl-CoA which is required for the de novo synthesis of fatty acids.
How does insulin regulate gluconeogenesis?
Insulin exerts direct control of gluconeogenesis by acting on the liver, but also indirectly affects gluconeogenesis by acting on other tissues. The direct effect of insulin was demonstrated in fasted dogs, where portal plasma insulin suppressed hepatic glucose production.
What is the normal function of pyruvate dehydrogenase kinase PDK?
Pyruvate dehydrogenase kinase (PDK) is a mitochondrial enzyme that is activated in a variety of cancers and results in the selective inhibition of pyruvate dehydrogenase, a complex of enzymes that converts cytosolic pyruvate to mitochondrial acetyl-CoA, the substrate for the Krebs’ cycle.
Is pyruvate dehydrogenase involved in gluconeogenesis?
Pyruvate Dehydrogenase complex (PDH) connects the citric acid cycle and subsquent oxidative phosphorylation to the glycolysis, gluconeogenesis and lipid and amino acid metabolism pathways.
How is the pyruvate dehydrogenase reaction regulated?
The pyruvate dehydrogenase complex is regulated by covalent modification through the action of a specific kinase and phosphatase; the kinase and phosphatase are regulated by changes in NADH, acetyl-CoA, pyruvate, and insulin.
What is the benefit of substrate channeling?
The physiological advantages of substrate channeling include control of metabolic flux, protection of reactive or toxic intermediates, increased catalytic efficiency, and decreased diffusion of intermediates away from the catalytic sites.
What does E3 do in PDH?
The protein encoded by the human PDHX gene, also known as E3 binding protein (E3BP), is part of the pyruvate dehydrogenase complex, a required complex for cellular respiration that catalyzes the dehydration of pyruvate to Acetyl-CoA.
How does insulin regulate glycogenolysis?
Regulation. Glycogenolysis is regulated hormonally in response to blood sugar levels by glucagon and insulin, and stimulated by epinephrine during the fight-or-flight response. Insulin potently inhibits glycogenolysis. In myocytes, glycogen degradation may also be stimulated by neural signals.
What is the function of PDK4?
PDK4 is increased in hibernation and helps to decrease metabolism and conserve glucose by decreasing its conversion to acetyl-CoA, which enters the citric acid cycle and is converted to ATP.
How is pyruvate dehydrogenase regulated?
How is hepatic gluconeogenesis regulated?
Hepatic gluconeogenesis is largely controlled in by transcriptional regulation of the enzymes which catalyze the key reactions of gluconeogenesis. Numerous transcription factors, including CREB, FOXO1, and C/EBPα/β, have been identified to stimulate the expression of PEPCK-C and G6Pase.
How does pyruvate dehydrogenase kinase 2/4 deficiency affect lactic acid?
Reduced lactic acid by pyruvate dehydrogenase kinase 2/4 (PDK2/4) deficiency resulting in the attenuation of neurological disorders. Glutaminase (GLS), monocarboxylate transporter (MCT), and PDK.
What is the role of glucokinase in the pathophysiology of glucose uptake?
Glucose is phosphorylated by glucokinase in hepatocytes to generate glucose 6-phosphate (G6P), leading to a reduction in intracellular glucose concentrations which further increases glucose uptake (Fig. 1). Moreover, G6P is unable to be transported by glucose transporters, so it is retained within hepatocytes.
What enzymes are involved in gluconeogenesis?
Gluconeogenesis is regulated by gluconeogenic enzymes. Gluconeogenic enzymes are regulated by posttranslational modifications and/or allosteric regulation. Most liver enzymes, which regulate glycolysis, gluconeogenesis, the TCA cycle, the urea cycle, and fatty acid and glycogen metabolism, are acetylated (292).