Glycogen Granules in a Hepatocyte

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Glycogen Granules in a Hepatocyte
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NOTE does this look familiar?
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Glucose 6-Phosphate can enter Glycolysis or be
hydrolyzed to glucose (within a liver cell).
Endoplasmic reticulum membrane physically
separates the hydrolysis reaction from glycolysis
reactions
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DG -19.2 kJ/mol
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Glycogen Synthesis
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Glycogenin Structure - Dimer
Mn2
UDP-Glucose
Tyrosine
Aspartic Acid
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Primed with 8 glucose residues
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Regulation of Metabolic Pathways

• Living Cells Maintain a Dynamic Steady State
• Regulatory Mechanisms Evolved under Strong
  Selective Pressures
• 12 of all genes code for regulatory machinary
  (human)
• 500 different protein kinases
• ATP and AMP regulatory systems are more
  common (table)

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Factors that determine the activity of an enzyme
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Coordinated Regulation of Glycolysis and
Gluconeogenesis
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Isozymes
Physiological glucose H1 is unaffected with
increasing glucose
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Phosphofructokinase-1 (PFK-1)- dimer blue ADP
yellow F1,6B (products) blue (interface)
ADP allosteric site
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L liver M muscle
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2 Fates of Pyruvate
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Both glycolysis and gluconeogenesis are regulated
by F26B -allosteric effector for PFK-1 and
FBPase-1
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Increased substrate affinity
Decreased substrate affinity
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Both PFK-2 and FBPase-2 are part of the same
peptide
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Predominates in resting muscle
Glycogen synthesis and breakdown are also
coordinated
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Enzyme Cascade
Discovered by Sutherland
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Liver phosphorylase has glucose sensor
Glycogen synthase can be phosphorylated by 11
different enzymes. GSK3 is the most important
(adds 3 phosphates). GSK3 must wait for casein
kinase II (CKII) to phosphorylate a different
residue before it can phosphorylate the 3
serines.
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GSK3 can be phosphorylated by a PKA or PKB which
makes it fold to look like the above picture.
This makes it inactive and will remain inactive
until the P is removed by a PP1
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Phosphatidylinositol 3 Kinase
Protein Kinases
Tyrosine -OH on an insulin receptor substrate
PIP2or3 phosphatidylinositol di-or tri-phosphate
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PP1 (phosphoprotein-1) is central to glycogen
metabolism -- dephosphorylates Phosphorylase
Kinase, Glycogen Phosphorylase and Glycogen
Synthase
Gm glycogen targeting protein Can be
phosphorylated in one or two positions
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