Nov 30, 2018

Tissue-specific kinase expression and activity regulate flux through the pyruvate dehydrogenase complex

The Journal of Biological Chemistry
Alla KlyuyevaKirill M Popov

Abstract

The pyruvate dehydrogenase complex (PDC) is a multienzyme assembly that converts pyruvate to acetyl-CoA. As pyruvate and acetyl-CoA play central roles in cellular metabolism, understanding PDC regulation is pivotal to understanding the larger metabolic network. The activity of mammalian PDC is regulated through reversible phosphorylation governed by at least four isozymes of pyruvate dehydrogenase kinase (PDK). Deciphering which kinase regulates PDC in organisms at specific times or places has been challenging. In this study, we analyzed mouse strains carrying targeted mutations of individual isozymes to explore their role in regulating PDC activity. Analysis of protein content of PDK isozymes in major metabolic tissues revealed that PDK1 and PDK2 were ubiquitously expressed, whereas PDK3 and PDK4 displayed a rather limited tissue distribution. Measurement of kinase activity showed that PDK1 is the principal isozyme regulating hepatic PDC. PDK2 was largely responsible for inactivation of PDC in tissues of muscle origin and brown adipose tissue (BAT). PDK3 was the principal kinase regulating pyruvate dehydrogenase activity in kidney and brain. In a well-fed state, the tissue levels of PDK4 protein were fairly low. In most tissue...Continue Reading

  • References39
  • Citations2

References

  • References39
  • Citations2

Citations

Mentioned in this Paper

Metabolic Process, Cellular
Study
Brown Fat
PDK4 protein, human
PDK2 protein, human
Ablation
Metabolic Networks
Regulation of Biological Process
WWC1
Pyruvate dehydrogenase

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