Long-term regulation and promoter analysis of mammalian pyruvate dehydrogenase complex

The PDC (pyruvate dehydrogenase complex) plays a central role in the maintenance of glucose homoeostasis in mammals. The carbon flux through the PDC is meticulously controlled by elaborate mechanisms involving post-translational (short-term) phosphorylation/dephosphorylation and transcriptional (long-term) controls. The former regulatory mechanism involving multiple phosphorylation sites and tissue-specific distribution of the dedicated kinases and phosphatases is not only dependent on the interactions among the catalytic and regulatory components of the complex but also sensitive to the intramitochondrial redox state and metabolite levels as indicators of the energy status. Furthermore, differential transcriptional controls of the regulatory components of PDC further add to the complexity needed for long-term tuning of PDC activity for the maintenance of glucose homoeostasis during normal and disease states.

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Starvation and diabetes increase the amount of pyruvate dehydrogenase kinase isoenzyme 4 in rat heart

Biochemical Journal ◽

10.1042/bj3290197 ◽

1998 ◽

Vol 329 (1) ◽

pp. 197-201 ◽

Cited By ~ 203

Author(s):

Pengfei WU ◽

Juichi SATO ◽

Yu ZHAO ◽

Jerzy JASKIEWICZ ◽

M. Kirill POPOV ◽

...

Keyword(s):

Pyruvate Dehydrogenase ◽

Rat Heart ◽

Insulin Treatment ◽

Pyruvate Dehydrogenase Complex ◽

Immunoblot Analysis ◽

Diabetic Rats ◽

Pyruvate Dehydrogenase Kinase ◽

Specific Effects ◽

Dehydrogenase Complex

This study investigated whether conditions known to alter the activity and phosphorylation state of the pyruvate dehydrogenase complex have specific effects on the levels of isoenzymes of pyruvate dehydrogenase kinase (PDK) in rat heart. Immunoblot analysis revealed a remarkable increase in the amount of PDK4 in the hearts of rats that had been starved or rendered diabetic with streptozotocin. Re-feeding of starved rats and insulin treatment of diabetic rats very effectively reversed the increase in PDK4 protein and restored PDK enzyme activity to levels of chow-fed control rats. Starvation and diabetes also markedly increased the abundance of PDK4 mRNA, and re-feeding and insulin treatment reduced levels of the message to that of controls. In contrast with the findings for PDK4, little or no changes in the amounts of PDK1 and PDK2 protein and the abundance of their messages occurred in response to starvation and diabetes. The observed shift in the relative abundance of PDK isoenzymes probably explains previous studies of the effects of starvation and diabetes on heart PDK activity. The results indicate that control of the amount of PDK4 is important in long-term regulation of the activity of the pyruvate dehydrogenase complex in rat heart.

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Long-term regulation of pyruvate dehydrogenase complex. Evidence that kinase-activator protein (KAP) is free pyruvate dehydrogenase kinase

Biochemical Journal ◽

10.1042/bj2750781 ◽

1991 ◽

Vol 275 (3) ◽

pp. 781-784 ◽

Cited By ~ 21

Author(s):

B S Jones ◽

S J Yeaman

Keyword(s):

Pyruvate Dehydrogenase ◽

High Speed ◽

Kinase Activity ◽

Pyruvate Dehydrogenase Complex ◽

Phosphorylation Site ◽

Pyruvate Dehydrogenase Kinase ◽

Activator Protein ◽

Major Phosphorylation Site ◽

Dehydrogenase Complex

The kinase-activator protein (KAP) of pyruvate dehydrogenase complex (PDC) has been purified approx. 2250-fold from high-speed supernatants of mitochondrial extracts from the liver of 48 h-starved rats. Purified KAP demonstrates kinase activity towards both the E1 component of PDC and towards a synthetic peptide corresponding to the major phosphorylation site on E1. Furthermore, the activities of KAP and PDC kinase co-fractionate through several stages of purification and have the same apparent mass. We conclude that KAP is not a distinct protein, but is kinase which has dissociated from the complex.

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