There are three basic ways to regulate the activity of an enzyme. The cell can control the synthesis of the enzyme by regulating the expression of the gene; the enzyme activity can be modified by binding small effector molecules that alter the structure of the enzyme (allosteric regulation); or the activity can be changed by covalent modification.
The activity of the pyruvate dehydrogenase complex (PDC) is controlled by the most common form of covalent modification, phosphorylation. There's an enzyme called pyruvate dehydrogenase kinase (PDH kinase, PDHK) that attaches phosphate groups to the E1 subunit of PDC. The phosphorylated form of PDC is inactive. Another enzyme called PDH phosphatase (PDP) removes the phosphate groups making the enzyme active again.
PDH kinase binds to the E2 subunits, specifically the lipoamide swinging arm [The Structure of the Pyruvate Dehydrogenase Complex]. There are four different PDH kinases and two different PDH phosphatases expressed in different tissues. Thus, the kinases and phosphatases are regulated, in part, at the level of gene expression. It turns out that they are also allosteric enzymes.
Knoechel et al. (2006) have looked at the structure of PHD kinase 2 (PDHK2) and located the sites of binding of several molecules that control activity of the kinase. One of the most important allosteric inhibitors is pyruvate. When pyruvate binds to PDH kinase 2 it blocks the kinase (phosphorylation) activity by changing the shape of the protein. Since phosphorylation of PDC doesn't occur, the pyruvate dehydrogenase complex remains active. Previously phosphorylated PDC becomes active because the phosphate is removed by PDH phosphatase.
The regulation makes sense. As pyruvate accumulates inside the cell you want to activate the pyruvate dehydrogenase complex in order to convert the pyruvate to acetyl CoA. As pyruvate levels fall the PDH kinase will no longer be inhibited and PDC will be inactivated by phosphorylation.
It wasn't possible to crystallize PDH kinase in the presence of pyruvate but it was possible to solve the structure of the enzyme with a similar molecule bound at the active site. The molecule is dichloroacetate (DCA) a molecule that inhibits PDH kinase by binding to the pyruvate site. Unlike pyruvate, DCA inhibition is pretty much irreversible.
Cancer cells often have inactivated pyruvate dehydrogenase complex for reasons that aren't clear (but see references in the link below). Treatment of cancer cells with DCA reactivates the pyruvate dehydrogenase complex and this leads eventually to the death of the cancer cells— at least in some cases. Unfortunately, dichloroacetate (DCA) is toxic so using it to treat cancer is a case of the cure being almost as bad as the disease.
This has not prevented growth of an underground economy in DCA by people who are desperate to cure their cancers. The situation is a mess. Read blogs by Abel Pharmboy at Terra Sigillata and Orac at Respectful Insolence for lots more information. There's a nice summary of their posts at Perversion of Good Science.
Pharmaceutical companies are very interested in finding a non-toxic inhibitor of PDH kinase 2. In fact, the paper by Knoechel et al. is mostly work done at Pfizer Ltd, in the UK. Their goal is to characterize as many inhibitors as possible.
Knoechel, T.R., Tucker, A.D., Robinson, C.M., Phillips, C., Taylor, W., Bungay, P.J., Kasten, S.A., Roche, T.E., and Brown, D.G. (2006) Regulatory roles of the N-terminal domain based on crystal structures of human pyruvate dehydrogenase kinase 2 containing physiological and synthetic ligands. Biochemistry 45:402-15. [doi: 10.1021/bi051402s]