Glycogen metabolism



Glycogen, is a sugar (carbohydrate) that is raised especially in liver and muscles. Glycogen is composed of a large number of glucose units. In the glycogen metabolism in the need of energy glycogen is broken down and by an excess of energy (glucose) glycogen is synthesised. In the glycogen metabolism, the glucose level is held on level in the blood. Glycogen is a fast available energy supply. After glycogen, fats (see fatty acid metabolism) and proteins (see amino acid metabolism) are utilised as an energy supply.
Below you find more (biochemical) information about the carbohydrate glycogen, about the structure and break down of glycogen and the regulation of the glycogen metabolism.

Glycogen
Glycogen break down
Glycogen synthesis
Regulation of glycogen metabolism



Glycogen


Glycogen is a soluble polymer of many glucose units.





Figure: Structure of two outside strands of glycogen. The green glucose unit is the beginning of a new strand. The red glucose units are not the reduced end. The R-groups is the rest of the glycogen molecule. The carbon atoms of glycogen are numbered as 1 to 6, this has been indicated with blue numbers.

In glycogen, glucose is stored as an energy supply. This glycogen is found in the liver and the muscle cells in so-called glycogen granules. In the liver cells the concentrations of glycogen are higher than in muscle cells, but the total quantities of glycogen stored in the muscles is larger than in the liver. This is because all the skeleton muscles together have a much larger mass than the liver on its own.
The word alpha, in the name of the bonds between the two glucose units, indicates that the two units are in a straight area. The numbers 1.6 and 1.4 mean that the bonds are between the carbon atoms 1 and resp. 4 and 6. By a low energy level (for instance by high effort), glycogen is broken down.
And when sufficient energy (glucose) is present this glucose is stored again as glycogen.


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Glycogen break down


If energy is needed, the energy supply in the form of glycogen is utilised.
The glycogen is hereby broken down in a way that a glucose-1-phosphate and a glycogen molecule with a glucose unit less arises. This process is called phosphorylyse. This literal means, break down by phosphate.
This break down reaction of glycogen is catalysed by phosphorylase (enzyme that catalyses the phosphorylyse).
This enzyme breaks the 1.4 bonds down at the non reduced end of the glycogen molecule.
The enzyme has PLP (pyridoxal 5'phosphate, originating from vitamin B6) necessary as an assistant-factor to let these break downs reaction to take place.


Figure: Reaction by which glycogen is converted in glucose-1-phosphate and glycogen with a glucose unit less. This reaction is catalysed by phosphorylase with as an assistant-factor vitamin B6.

In this manner, the 1.4 bonds are broken. With the 1.6 bonds, it is different. The enzyme phosphorylase cannot break the 1.6 bonds. Here some other method is necessary. What happens is that the phosphorylase first breaks the 1.4 bonds of the glycogen until 4 glucose units before the junction.



Phosphorylase breaks the 1.4 bonds off until 4 units for the junction (blue balls off).





Now some other enzyme comes in action, a transferase. This transferase set a block of 3 glucose units of one strand over to the other strand. This does the enzyme by breaking first the 1.4 bond in one strand and to form a new in the other strand.





Now a third enzyme (alpha 1,6-glucosidase also called debranching enzyme) can break the 1.6 bond (the green ball get off). This does the enzyme by to hydrolyse the 1.6 bond (break using water).
Hereby arises glucose (no glucose-1-phosphate) and a glycogen molecule with a glucose unit less.



Figure: The breaking (hydrolyse) of the 1.6 bond of the glycogen by the debranching enzyme.

The hereby synthesised glucose must be first phosphorylised till glucose-6-phosphate to be broken down in the glycolysis.
If the 1.6 bond is broken the phosphorylase can go further to break down the 1.4 bonds.



Figure: The phosphorylase can go further again to break the 1.4 bonds.

It is an advantage that glycogen is branched (with the 1.6 bonds), because the phosphorylase enzyme can break the glycogen on more places at the same time. Also glycogen is better soluble as it is more branched.
By the phosphorylation of glycogen, there are arise a number glucose-1-phosphate molecules.
These molecules can not yet be broken down further in the glycolysis. Firstly, to be able to be broken down, this must be converted into glucose 6-phosphate. This glucose 6-phosphate is possible to be broken down in the glycolysis. This reaction is catalysed by phosphoglucomutase.
The active side contain a phosphorylated serine residue. This serine can deliver its phosphate at glucose-1-phosphate, so that glucose-1,6-bisphosphate arises. The not phosphorylated serine takes a phosphate group, and then glucose-6-phosphate arises. This can be processed in the glycolysis.


Figure: Transformation of glucose-1-phosphate to glucose-6-phosphate by a mutase.

The formed glucose-6-phosphate can no longer leaf the cell because a phosphate group at is attached.
The livers is an organ that regulates the sugar (glucose) level in your blood. If the muscles work hard the sugar levels go down, because the muscles use many fuel (glucose). The brains work exclusively on glucose.
The liver brings the glucose levels back on level to break first glycogen down and there, as discussed, glucose-6-phosphate is made. This glucose-6-phosphate cannot get out of the cell, it could if the phosphate group gets off.
The liver has an enzyme that can get off this phosphate group. This enzyme, that lies in the "endoplasmatic reticulum" in the cell, is called glucose-6-phosphatease.
This enzyme catalyses the following reaction:

Glucose-6-phosphate + H2O Glucose + Phosphate

Now the phosphate group off is can the glucose the cell from and in the blood be taken up. The kidneys have, like the liver, also the enzyme glucose- 6-phosphatease. The liver and the kidneys can thus glucose from their cells transports.
Organs as the skeleton muscles and the brains know this enzyme not in their cells, they can glucose thus not from their cells transports. This comes because when these cells glucose in their cell got, they this not gladly more deliver.
These cells use glucose as most important fuel.


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Glycogen synthesis


If sufficient glucose is present it will be stored in glycogen. Glycogen is composed thus of glucose units.
Firstly for this glucose-1-phosphate at UTP (Uridine Tri Phosphate) is coupled. By this reaction, UDP-Glucose (Uridine Tue Phosphate-glucose) arises and pyrophosphate (PPi). The reaction is catalysed by the enzyme UDP-glucose pyrophosphorylase.



Figure: The clutch of glucose-1-phosphate at UTP so that it UDP-glucose and PPi arises.

In the body the formed PPi is broken fast until two phosphates, this is catalysed by pyrophosphatase:

PPi + H2O 2Pi

Because this PPi at the same time is broken the balance of the reaction of glucose-1-phosphate and UTP lies strongly to right. So that the reaction can remain lapse good, and it is formed thus good UDP-glucose.

The UDP-glucose can be coupled to a glycogen molecule with at least 4 glucose units.

Because of this the glycogen molecule will be one glucose unit longer. This reaction is catalysed by glycogen synthase.



Figure: The binding of UDP-glucose at a glycogen molecule by glycogen synthase.

By this reaction thus always a beginning of glycogen is necessary with at least 4 units. If in very extreme cases all the glycogen on then has the cell always some other "start briskly". For this "start briskly" is the enzyme glycogenin.
On the manner as until now closed described there only arise alpha 1.4 bonds. Glycogen contain also alpha 1.6 bonds.
This alpha 1.6 bonds arise because an enzyme (the branching enzyme) the alpha 1.4 bonds broken cuts and a new alpha 1.6 bond makes. This puts on after approximately 10 units. The advantage of branched glycogen is that it has a better solubility and that it can be broken down faster.
By the raising of energy (glucose) in glycogen and it later on again break of glycogen goes about 3% energy lost, compared with direct use of glucose. This is a small percentage lose, and this makes one efficient form of energy raise.


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Regulation of glycogen metabolism


The two different pathways for synthesis and break down of glycogen must be well regulated.
If both pathways would work at the same time needlessly many ATP will be consumed. If glycogen must be built up or broken is determined by if many or little glucose is present in the organism.
This is among other things regulated by hormones like: insulin, epinephrine and glucagon.
The phosphorylase (enzyme that breaks glycogen) in skeleton muscles occur in two forms. An active, phosphorylase a and a not active phosphorylase b. Phosphorylase b is converted in phosphorylase a by phosphorylation (a phosphate group to it set) of a serine residue on the phosphorylase b. This reaction is catalysed by phosphorylase kinase.



Figure: The convertion of a not active to an active phosphorylase by phosphorylase kinase.

The phosphorylase a can be transformed by hydrolyse of the phosphorylated serine residue again till phosphorylase b.
This reaction is catalysed by protein phosphatase 1.
Normal phosphorylase b will always be inactive (there is no glycogen broken down). In utmost extreme cases, phosphorylase b nevertheless can get active. This lifted then because almost all the energy is finished, then can the cell it no phosphorylase a more make because all the ATP is finished. If there is little energy, there are higher concentrations AMP present in the cell, and lower concentrations ATP and glucose-6-phosphate. Normally there is sufficient ATP and glucose-6-phosphate present so that these compounds hold the phosphorylase b in the inactive form. If these compounds are almost finished and there is many AMP formed, then the phosphorylase b can change so that it gets active (not by phosphorylation only by allosteric modification).
Phosphorylase b (inactive) can be converted in phosphorylase a (active) under influence of hormones (Epinephrine, Glucagon). By these hormones, a cascade can turn active.


Epinephrine
Adenylate Adenylate
cyclase               cyclase
                                ATP Cyclic
                                                  AMP
                                                 Protein    Protein
                                                  kinase A               kinase A
                                                                       phosphorylase      phosphorylase
                                                                   kinase                          kinase
                                                                                                    Phosphorylase  Phosphorylase
                                                                                                         b                         a

Figure: Transformation of inactive phosphorylase b into active phosphorylase a by the cyclical AMP cascade.

The hormone epinephrine binds on a particular receptors on muscle cells and glucagon on receptors in liver cells.
At the moment that this hormone binds at the receptor the above cascade active.
Red is inactive and is active is green. Finally thus the inactive phosphorylase b is converted into active phosphorylase a by the phosphorylase kinase. The glycogen is broken by phosphorylase a and comes there glucose free. In the liver, the glucose is delivered at the blood, and the sugar rises reflect. In the muscles, there is to be burnt more glucose.
The use of such cascade is that it a large reinforcement acts. Each enzyme can form many substratum (e.g. protein kinase A forms active phosphorylase kinase). And each formed substratum is prevent on its turn an enzyme that again new substratum form can (e.g. phosphorylase kinase forms phosphorylase a). This cascade gives a reinforcement of approximately 1,000,000,000 (10 till the 9e). Hormones come in the blood for in a concentration of approximately 0,000000008 mmol/l, and glucose in approximately 8 mmol/l.
The regulation of glycogen synthesis by hormones gives a partial equal cascade then that for glycogen break down.


Epinephrine
Adenylate Adenylate
cyclase               cyclase
                               
ATP Cyclic
                                                  AMP
                                                 Protein    Protein
                                                  kinase A               kinase A
                                                                              Glycogen      Glycogen
                                                                               synthase a                synthase b

Figure: Transformation of active glycogen synthase a in inactive glycogen synthase b by the cyclical AMP cascade.

Green is again active and red inactive. By the binding of epinephrine glycogen synthase a (active) is converted into glycogen synthase b (inactive). Protein kinase puts a phosphate group to the active glycogen synthase a so that it gets inactive (glycogen synthase b). By the binding of the hormone thus the break down of glycogen becomes active and the synthesis is, by glycogen synthase, stopped. This is because protein kinase A has two substrata namely: Inactive phosphorylase kinase and active glycogen synthase a.
If the sugar levels in the blood went down first the synthesis of glycogen stops and start after that fit defence the break down.
This is because the affinity of the protein kinase A for glycogen synthase a is larger then for the inactive phosphorylase kinase. Firstly glycogen synthase a is converted into glycogen synthase b (synthesis stops). And after that inactive phosphorylase kinase is converted into active phosphorylase kinase by which phosphorylase b is converted into phosphorylase a (the break down start).

Graphics energy / synthesis and break down glycogen

Figure: As a result of an increase of energy firstly the synthesis stops and after that the break down (phosphorylase) of glycogen start.

And the other way as the blood sugar level rises firstly the break down is stopped and after that the synthesis is started. This stop of the break down and start of the synthesis is accomplished by the enzyme protein phosphatase 1. This enzyme is made active by the hormone insulin.

Graphics energy / synthesis and break down glycogen

Figure: As a result of a drop in energy firstly the break down (phosphorylase) stops and after that the synthesis of glycogen starts.

[1]. Stryer, Lubert;- Biochemistry - fourth edition; New York: W. H. Freeman and Company (1995). ISBN 0-7167-2009-4


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