5.1.2 Regulation of pyruvate dehydrogenase
Pyruvate is used in various pathways:
- It can be turned into acetyl-CoA for complete degradation, or for lipid synthesis;
- it can be carboxylated to yield oxaloacetate, to be used either in gluconeogenesis or in the citric acid cycle;
- it can be used for the synthesis of amino acids. For example, a single transamination reaction turns pyruvate into alanine.
It is clear then that the activities of all enzymes that act on pyruvate, including pyruvate dehydrogenase, have to be regulated in accord with the prevailing metabolic needs. Pyruvate dehydrogenase is subject to two modes of regulation (Figure 5.1.2-1):
- Allosteric control1. Pyruvate dehydrogenase is stimulated by Fructose-1,6-bisphosphate but inhibited by NADH and Acetyl-CoA.
- Phosphorylation by a special regulatory enzyme, pyruvate dehydrogenase kinase. This enzyme is tightly bound to the pyruvate dehydrogenase complex. Phosphorylation inactivates pyruvate dehydrogenase. The kinase, in turn, is allosterically activated by NADH and Acetyl-CoA but inhibited by ADP, NAD+ and by free coenzyme A.
- Phosphorylation is reversed, and the activity of pyruvate dehydrogenase restored by a phosphatase, which is also associated with the pyruvate dehydrogenase complex.
This phosphatase is activated by calcium ions. You may recall that calcium ions are also involved in triggering the contraction of muscle cells. Each of these regulatory effects makes good physiological sense—it would be a worthwhile exercise for you to figure out what sense.
1: If you are unsure what this means, you should have a look at section 2.5 or better yet, your textbook.