EVIDENCE FOR EXISTENCE OF TISSUE-SPECIFIC REGULATION OF THE MAMMALIANPYRUVATE-DEHYDROGENASE COMPLEX

Tissue distribution and kinetic parameters for the four isoenzymes of pyruvate dehydrogenase kinase (PDK1, PDK2, PDK3 and PDK4) identified t hus far in mammals were analysed. It appeared that expression of these isoenzymes occurs in a tissue-specific manner. The mRNA for isoenzyme PDK1 was found almost exclusively in rat heart. The mRNA for PDK3 was most abundantly expressed in rat testis. The message for PDK2 was pre sent in all tissues tested but the level was low in spleen and lung. T he mRNA for PDK4 was predominantly expressed in skeletal muscle and he art. The specific activities of the isoenzymes varied 25-fold, from 50 nmol/min per mg for PDK2 to 1250 nmol/min per mg for PDK3. Apparent K -i values of the isoenzymes for the synthetic analogue of pyruvate, di chloroacetate, varied 40-fold, from 0.2 mM for PDK2 to 8 mM for PDK3. The isoenzymes were also different with respect to their ability to re spond to NADH and NADH plus acetyl-CoA. NADH alone stimulated the acti vities of PDK1 and PDK2 by 20 and 30% respectively. NADH plus acetyl-C oA activated these isoenzymes nearly 200 and 300%. Under comparable co nditions, isoenzyme PDK3 was almost completely unresponsive to NADH, a nd NADH plus acetyl-CoA caused inhibition rather than activation, Isoe nzyme PDK3 was activated almost 2-fold by NADH, but NADH plus acetyl-C oA did not activate above the level seen with NADH alone. These result s provide the first evidence that the unique tissue distribution and k inetic characteristics of the isoenzymes of PDK are among the major fa ctors responsible for tissue-specific regulation of the pyruvate dehyd rogenase complex activity.