REGULATION OF PYRUVATE DEHYDROGENASE KINASE

Project: Research project

Description

Recent work from this laboratory provide evidence for a new family of
protein kinases in eukaryotic cells. These kinases show no sequence
similarity with other eukaryotic protein kinases, but are related to the
histidine protein kinases previously thought to be present only in
prokaryotic cells. A member of this family corresponding to the pyruvate
dehydrogenase (PDH) kinase, responsible for phosphorylation and
inactivation of the mitochondrial PDH complex, has been cloned. A high
titer antiserum against a recombinant PDH kinase fusion protein has also
been generated. Previous work indicates that long term regulatory
mechanisms are involved in control of PDH kinase activity, and,
therefore, the proportion of the PDH complex in the active,
dephosphorylated state. Mechanisms responsible for regulation of PDH
activity are important because of the central role of this complex in
carbohydrate metabolism. Our working hypothesis is that isozyme of PDH
kinase exist and that long-term control mechanisms differentially affect
the amounts and the specific activities of the isozyme. The hypothesis
will be tested in experiments proposed with purified enzymes, recombinant
enzymes, and tissues obtained from rats and humans. The specific aims
are to determine the molecular basis for (a) the presence of free and
bound forms of PDH kinase; (b) the differences in the relative amounts
of PDH kinase activity in liver, heart, kidney, muscle, brain, adipose
tissue and tumor cells; and (c) changes in the relative amounts of PDH
kinase activity induced by starvation and diabetes in the rat and by type
II diabetes in man. The proposed work will contribute significantly to
our understanding of mechanisms regulating fuel selection in
mitochondria-containing tissues of the body. We should discover why PDH
kinase activity increases in tissues of starved and diabetic animals,
andy why the PDH complex is resistant to regulation by covalent
modification in tumor cells. Since PDH kinase is a possible target for
therapeutic intervention, the proposed work is relevant to the
development of strategies for the treatment of diabetes, obesity,
atherosclerosis, sepsis, and cancer.
StatusFinished
Effective start/end date6/1/9412/31/09

Funding

  • National Institutes of Health: $327,872.00
  • National Institutes of Health
  • National Institutes of Health: $236,062.00
  • National Institutes of Health: $311,779.00
  • National Institutes of Health: $173,699.00
  • National Institutes of Health: $230,707.00
  • National Institutes of Health: $335,872.00
  • National Institutes of Health
  • National Institutes of Health: $225,507.00
  • National Institutes of Health
  • National Institutes of Health: $324,615.00
  • National Institutes of Health: $220,573.00
  • National Institutes of Health: $318,255.00
  • National Institutes of Health: $160,594.00

Fingerprint

Pyruvate Dehydrogenase Complex
Isoenzymes
Insulin
Glucose
Phosphotransferases
Homeostasis
pyruvate dehydrogenase (acetyl-transferring) kinase
Glucocorticoids
Carbon
Pyruvate Dehydrogenase (Lipoamide)-Phosphatase
Fasting
Phosphorylation
Pyruvic Acid
Protein Kinases
Phosphoric Monoester Hydrolases
Starvation
Nonesterified Fatty Acids
Type 2 Diabetes Mellitus
Gene Expression
Up-Regulation

ASJC

  • Medicine(all)