Pyruvate dehydrogenase complex control

Regulation of the Pyruvate Dehydrogenase Complex Control of the Citric Acid Cycle (Figure 14.3) (Summary)... 

A second advantage of a multienzyme complex is that regulatory controls can be applied more efficiently in such a system than in a single enzyme molecule. In the case of the pyruvate dehydrogenase complex, controlling factors are intimately associated with the multienzyme complex itself, which we shall study in Section 19.5. 

Ravindran, S., Radke, G.A., Guest, J.R. and Roche, T.E. (1996) Lipoyl domain-based mechanism for the integrated feedback control of the pyruvate dehydrogenase complex by enhancement of pyruvate dehydrogenase kinase activity. Journal of Biological Chemistry 271,653-562. 

Control of the activity of the pyruvate dehydrogenase complex is exerted by the phosphorylation of pyruvate decarboxylase (E[), which renders it inactive. This process is catalyzed by pyruvate dehydrogenase kinase, which is always tightly bound to E[. The kinase is activated by high-energy conditions, and it requires ATP to accomplish the phosphorylation step. Another enzyme, phosphoprotein phosphatase, is weakly bound to E, and reactivates the system by removing the inhibitory phosphate group (Fig. 12-8). 

The pyruvate dehydrogenase complex is not directly a part of the reactions that constitute the citric acid cycle. It is the link between glycolysis and the citric acid cycle, and its activity is controlled by the energy status of the mitochondria. 

Fig. 12-8 The control of the pyruvate dehydrogenase complex via phosphory-lation/dephosphorylation of the pyruvate decarboxylase part of the complex.

The citric acid cycle, also known as the tricarboxylic acid cycle or the Krebs cycle, is the final oxidative pathway for carbohydrates, lipids, and amino acids. It is also a source of precursors for biosynthesis. The authors begin Chapter 17 with a detailed discussion of the reaction mechanisms of the pyruvate dehydrogenase complex, followed by a description of the reactions of the citric acid cycle. This description includes details of mechanism and stereospecificity of some of the reactions, and homologies of the enzymes to other proteins. In the following sections, they describe the stoichiometry of the pathway including the energy yield (ATP and GTP) and then describe control mechanisms. They conclude the chapter with a summary of the biosynthetic roles of the citric acid cycle and its relationship to the glyoxylate cycle found in bacteria and plants. 

The reactions catalysed by the pyruvate dehydrogenase complex (PDH) irreversibly commit the carbon skeleton of glucose to ultimate oxidation by the reactions of the citrate cycle either directly or via the formation of fatty acids. It is not surprising therefore to find that such an important reaction is under close control. Thus it is subject to ... 

Within many tissues the enzymatic activities of the pyruvate and branched chain oxoacid dehydrogenases complexes are controlled in part by a phosphorylation -dephosphorylation mechanism (see Eq. 17-9). Phosphorylation of the decarboxylase subunit by an ATP-dependent kinase produces an inactive phosphoenzyme. A phosphatase reactivates the dehydrogenase to complete the regulatory cycle (see Eq. 17-9 and associated discussion). The regulation is apparently accomplished, in part, by controlling the affinity of the protein for... 

The pathways of metabolism have multiple control points and multiple regulators at each control point. The function of these complex mechanisms is to produce a graded response to a stimulus and to provide sensitivity to multiple stimuli so that an exact balance is maintained between flux through a given step (or series of steps) and the need or use for the product. Pyruvate dehydrogenase is an example of an enzyme that has multiple regulatory mechanisms. Regardless of insulin levels, the enzyme cannot become fully activated in the presence of products and absence of substrates. 

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