BIOGENESIS OF GLYCOGEN

Project: Research project

Project Details

Description

This is a study of a unique event in enzymology, involving a protein we
first characterized in 1985 that is the key to a process fundamental to
survival in higher forms of life, the synthesis of glycogen. The protein
is glycogenin. Its amount and location control the amount of glycogen the
cell can synthesize and where the glycogen is deposited, and its presence
in a functioning form seems essential for the economy of the cell.
Therefore we need to understand glycogenin's key role in the biogenesis of
glycogen. The protein is unique in that it is autocatalytic. By using
UDPglucose to attach a chain of glucose units to itself-the first one via
a novel bond to tyrosine -glycogenin creates the priming chain on which
glycogen synthase and branching enzyme build glycogen. Glycogenin remains
part of the glycogen as a cryptic enzyme and, if released by glycogen
depletion, becomes active again, ready to help restore glycogen. We wish
to know how glycogenin synthesis is regulated, whether its activity is
controlled by covalent modification (phosphorylation/dephosphorylation) and
the location on the peptide chain of the several important functional
sites, Mn2+ -binding (Mn2+ is an activator), the UDPglucose-binding site
and the site(s) where inhibitory nucleotides bind. Progress has been
greatly assisted by the ability to express wild-type and mutant
glycogenins. in the coming project period we will use our array of
recombinant proteins to study the structure and functioning of Glycogenin.
Then we will examine how it interacts with glycogen synthase and try to
define the complex that
it has been claimed, is essential for glycogen synthesis to take place.
This will include a study of a new form of glycogen synthase we discovered,
that acts between glycogenin and the already known synthase to synthesize
a second, intermediate 400 kDa form of glycogen, proglycogen, which goes on
to become depot glycogen. In parallel tot he in vitro experiments, we will
employ the immature frog oocyte as a "living test tube" in which to study
glycogenin and its participation in glycogen synthesis. The oocyte's own
rudimentary glycogen synthesizing system is ideally suited to this purpose.
Overall, our aim is to define precisely the initial events in glycogen
synthesis. pursuing health related matters, we are localizing sequencing
the human gene for glycogenin. We regard glycogenin as a plausible, so-
far-untested candidate enzyme, aberrations in which may cause the
abnormalities of glycogen metabolism seen in Type II diabetes. Using blood
from Type II patients we will search for possible mutations in the
glycogenin gene and attempt to express and study any glycogenin mutant
thereby detected. Our work also has direct interest for exercise
physiology and sports medicine in terms of the advantages of glycogen
supercompensation for endurance. Glycogenin and proglycogen are the keys
to supercompensation.
StatusFinished
Effective start/end date12/31/898/31/99

Funding

  • National Institute of Diabetes and Digestive and Kidney Diseases
  • National Institute of Diabetes and Digestive and Kidney Diseases
  • National Institute of Diabetes and Digestive and Kidney Diseases
  • National Institute of Diabetes and Digestive and Kidney Diseases
  • National Institute of Diabetes and Digestive and Kidney Diseases
  • National Institute of Diabetes and Digestive and Kidney Diseases
  • National Institute of Diabetes and Digestive and Kidney Diseases
  • National Institute of Diabetes and Digestive and Kidney Diseases
  • National Institute of Diabetes and Digestive and Kidney Diseases
  • National Institute of Diabetes and Digestive and Kidney Diseases
  • National Institute of Diabetes and Digestive and Kidney Diseases

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