Glycogen and GSD Flashcards
An extended and branched polymer of glucose, with each granule having a molecular weight in excess of 2000 kDa
Glycogen
Glucose residues are joined in a linear chain by
a-1,4 glycosidic bonds
The branch points of glycogen, which occur, on average, every 10 or so residues, have an
a-1,6-glycosidic bond
Composed of very long linear polymers of glucose, but in a B-1,4 linkage
Cellulose
In plants, starch functions for energy storage, while cellulose has a
Structural role
Represents one of the two basic forms in which the chemical energy derived from foods is stored
Glycogen
The two largest reservoirs of glycogen in the body
Muscle and Liver
Mobilized in the early phases of a fast, in order to maintain blood glucose levels
Liver Glycogen stores
In most individuals, liver glycogen stores can meet this need for between
12-24 hours
CANNOT contribute to the maintenance of blood glucose levels, but instead are utilized as a site specific energy source
Muscle glycogen stores
The major intersection in the glucose metabolism road map
Glucose-6-phosphate
Converts glucose-6-phosphate to glucose-1-phosphate
Phosphoglucomutase
Glucose 1-phospate becomes the substrate for
-adds a UMP portion while releasing pyrophosphate (PPi)
UDP-glucose phosphorylase
The resultant UDP-glucose is the immediate precursor in glycogen polymer extension, carried out by
Glycogen Synthase
Polymerizes glucose residues by catalyzing the formation of the a-1,4-linkages
Glycogen synthase
Addition of each glucose residue is coincident with release of its
UDP carrier
Glycogen synthase cannot create branch structures, however. This task is the responsibility of the
Branching enzyme
NOT a substrate for this enzyme
UDP-glucose
Able to transfer a five- to eight-mer of a linear glycogen polymer to another glucose residue ‘upstream’ on the polymer chain, forming the alternative a-1,6 linkage
Branching Enzyme
This creates a new polymer growing end and thus an additional substrate upon which glycogen synthase can act to elongate the
Glycogen Chain
Cannot initiate polymer synthesis. It can only add to a pre-existing polymer
Glycogen Synthase
Has several critical roles in the initiation of glycogen synthesis
Glycogenin
The hydroxyl moiety of a tyrosine residue in glycogenin serves for the formation of the first
Glycosidic bond
Importantly, this first glucose residue is attached not by glycogen synthase but by an enzymatic activity in
Glycogenin
After the polymer is at least eight residues long, polymerization occurs via
Glycogen Synthase
Apart from the ATP that is required to phosphorylate free glucose, one additional ATP is required for each glucose residue added to the
Polymer
This ATP is consumed by
-carries out the reaction UDP + ATP –> UTP + ADP
Nucleoside diphosphate kinase
Echoing patterns in both glycolysis/gluconeogenesis and in fatty acid synthesis/B oxidation, glycogen breakdown is not simply the reverse of
Glycogen Synthesis
Not an intermediate in glycogen breakdown
UDP-Glucose
Importantly, it is in the breakdown of glycogen that the liver and muscle
Differ
Glycogen breakdown begins at the many branch ends of the molecule, with the action of
Glycogen Phosphorylase
Inorganic phosphate is recruited in this reaction, producing
Glucose-1-phosphate
Glucose 1-phosphate is subsequently isomerized to glucose 6-phosphate by
Phosphoglucomutase
The only enzyme the synthetic and degradative pathways share
Phosphoglucomutase
In analogy to glycogen synthase, glycogen phosphorylase cannot attack the
a-1,6-linkage at branch points
In fact, phosphorylase halts its progressive release of gluocse 1-phosphate molecules how many residues before a branch?
Four
Branch removal is a 2-step process. The first step is catalyzed by the
Debranching enzyme (glucosyl (4:4) transferase)
This enzyme transfers three of those four residues to another non-reducing end, in a single catalytic step, via conventional
a-1,4-linkages
This leaves only one glucose residue in a
a-1,6-linkage
The second step is catalyzed by amylo-(a-1,6)-glucosidase, which releases
Free glucose
We will call this second enzymatic activity ‘debranching enzyme’ as well, because, in fact, both enzymatic activities dealing with breakdown of branch structures are present on
One polypeptide
The result of glycogen mobilization in all tissues is the release, predominantly, of
Glucose-1-phosphate
Able to remove the phosphate residue to liberate free glucose
Liver glucose-6-phosphatase
Free glucose can in turn enter the circulation, thereby contributing to the maintenance of
Blood glucose
In contrast, muscle lacks this phosphatase, so product gluose 6-phosphate is shunted directly into
Glycolysis for ATP production
Remember that a modest quantity of free glucose is produced in muscle glycogen breakdown via the second step catalyzed by
De-branching enzyme
While liver glycogen supplies serve to maintain blood glucose levels in the early stages of a fast, muscle glycogen does not, due to the absence of a muscle
Glucose-6-phosphatase
What are the energy expenditures in mobilization of glycogen?
None
Uses inorganic phosphate, not ATP, to produce glucose 1-phosphate
Glycogen phosphorylase
The key enzymes targeted to regulate glycogen synthesis and breakdown are
Glycogen synthase and glycogen phosphorylase
Hormonal regulation in the liver is mediated by
Insulin and glcucagon
Hormonal regulation in the muscle is mediated by
Insulin and epinephrine
Undergo covalent modifications that variously stimulate or inhibit their activity
Glycogen synthase and phosphorylase
In exercising muscle, Ca2+ comes into play, and glycogen mobilization can reach very high rates in a matter of only a few
Seconds
However, these changes can also be long lasting. Liver glycogenolysis is a process that may go on, uninterrupted, for
12 hours or more during fasting
Contrasting the insulin/glucagon/epinephrine regulatory input is what we’ll call ‘local’ regulation via small molecule
Allosteric effectors
During the early stages of a fast, and periods of muscle activity, the trend will be to
Activate the phosphorylase and inhibit the synthase
For the energy poor state, what is the
- ) Hormonal signal?
- ) Intracellular signal?
- ) GLucagon
2. ) AMP
Signal periods of muscle activity in skeletal muscle
Ca2+ and epinephrine
The energy-poor hormonal signaling pathway in liver begins with the binding of glucagon to its
Membrane bound receptor
The receptor activates an adenylate cyclase, causing an increase in intracellular
cAMP concentration
cAMP in turn activates a
cAMP-dependent protein kinase
Phosphorylates glycogen synthase-a, converting it to the inactive “b” form
cAMP-dependent protein kinase
In fact, glycogen synthase is able to accept as many as
-number of phosphatases determines degree of inhibition
9 phosphatases
This same cAMP-dependent protein kinase also activates a second protein kinase, known as
Phosphorylase kinase
In turn is able to convert inactive glycogen phosphorylase-b to the active (phosphorylated) a form
Phosphorylase kinase
The net effect is the shut down of glycogen synthesis and the activation of
Glycogenolysis
Nervous stimulation of muscle includes membrane bound receptor binding of
Epinephrine
Nervous stimulation of muscle includes binding of epinephrine to its membrane-bound receptors as well as the release of sarcoplasmic stores of
Ca2+
Epinephrine’s stimulation of muscle glycogenolysis follows the cascade already described for
Glucagon
Importantly, Ca++ binding to the calmodulin subunit of phosphorylase kinase stimulates its activity to phosphorylate
Glycogen phosphorylase
This signaling can be done inthe absence of
cAMP
As muscle relaxes, free intracellular Ca++ levels drop and the phosphorylase kinase is again deactivated by
Calmodulin
Reverse the modifications made by phosphorylase kinase and the mobilization of glycogen halts once again
Cellular phosphatases
On the local level, muscle glycogen phosphorylase is allosterically
- ) Activated by (indicator of energy defecit)?
- ) Inhibited by (indicator of energy abundance)?
- ) AMP
2. ) Phosphocreatine
A good example of local regulation “trumping” hormonal regulation is shown here, where AMP can activate the
Unphosphorylated enzyme
Conversely, the active, phosphorylated form can be locally inhibited by
ATP and Glucose-6-phosphate
During energy-rich periods, and periods of muscle inactivity, the trend will be to
Activate the synthase and inhibit the phosphorylase
What are the principal molecular signals of an energy rich state?
Insulin, G-6-P, Glucose, and ATP
The energy-rich state is signaled by a high
Insulin to glucagon ratio
Increasing this ratio stimulates glycogen synthesis over its
Degredation
In liver and muscle, efficient insulin binding to its receptor activates a
Tyrosine Kinase
This kinase in turn activates another kinase, whose ultimate target is
Protein Phosphatase 1 (PP1)
Removes inhibitory phosphates from glycogen synthase (converting it back to the active “a” form), as well as removing the activating phosphate(s) from glycogen phosphorylase (converting it to the inactive “b” form)
PP1
The net effect, therefore, of insulin signaling, is to
Activate glycogen synthase
Inhibit glycogen phosphorylase
In terms of local allosteric regulation, high levels of glucose 6-phosphate, signaling an energy rich state, allosterically
Activate glycogen synthase and inhibit glycogen phosphorylase
Is also able to inhibit glycogen phosphorylase
ATP
These effects are largely independent of the phosphorylation state of glycogen synthetase, and thus constitute a parallel regulatory mechanism that operates on local and short-term scales and is able to override
Hormonal input
There are atleast 9 different deficiencies in glycogen metabolism. These are referred to as
Glycogen storage diseases or Glycogenoses
