Glycogenesis

If you’ve ever heard of glycogen, via this site, school, or somewhere else, you understand that glycogen is a massive reason why our body is able to function in various circumstances. From having an existence between meals to high intensity activity, glycogen is the key player to these facets of our existence. If you are not familiar with this, I would recommend reading a general article on glycogen to grasp greater context. Glycogen, however, does not appear from thin air; it occurs in the body via a process called glycogenesis and in this article, we will learn everything there is to know about this process. I will offer as much context and real world application to the chemical happenings of glycogenesis as I possibly can while not sacrificing the detail this subject deserves. 

What is glycogenesis?
Glycogenesis, in its simplest definition, is the creation of glycogen from glucose.

Where does it occur?
Glycogenesis occurs, primarily, in the liver and muscle cells as those are both the primary glycogen sites.

Why does it matter?
As glycogen is imperative for high intensity activity (weight lifting, sprinting, anaerobic activity) and also regulates blood sugar, it cannot be overstated how important glycogen is to our physiology (11).

How does glycogenesis occur?
Now that we have a bit of background, we can delve into the complexities of what our body does to ensure that glycogenesis occurs to do all the wonderful things it is meant to do for us. This will be best understood, as many biochemists explain it, in steps. However, I will attempt to explain things a bit more “real world-y” than just pure science which can get a bit overwhelming. Shall we begin?

                                                                    Step 1: Glucose --> Glucose-6-Phosphate

Our body runs on glucose and as such breaks food down to a usable glucose form in the blood stream. However, once glucose is shuttled into the cell, it goes through many steps, to change the molecular structure of glucose to a more efficient one, before being ready to be used for various processes.  As glucose crosses the cell membrane and enters the cytoplasm, the structure of the glucose needs to be changed so that it does not diffuse back across the membrane – this renders it, in a manner of speaking, more unstable so that further processes can be acted upon glucose now turned Glucose-6-Phosphate (4).  All of these metabolic processes follow this first step, so let’s examine it.

Sub-step 1: Glucose enters the cell to begin the first step of glycolysis.

 

Cell Cytoplasm (Inside Cell - Glycolysis)

Cell membrane

What is glycolysis?
One of the three metabolic processes that supply us with energy from the breakdown of glucose.

Where does glycolysis occur?
Right in the cytoplasm of the cell, which makes sense in this case considering glycogen is stored in the cytoplasm.

Sub-step 2: Hexokinase or Glucokinase phosphorylates, by way of Adenosine Tri-Phosphate (ATP), glucose to make Glucose-6-Phosphate. The addition of ATP makes this an energy releasing process as the ATP phosphorylates glucose to create Glucose-6-Phosphate; ATP is then changed to Adenosine Di-Phosphate (ADP).



 

What are Hexokinase and Glucokinase?
Hexokinase and Glucokinase are both enzymes whose sole purpose is to act on glucose in the above example. They do this by phosphorylation (explained below). The difference between these two enzymes is that Hexokinase is found in muscle glucose metabolism while Glucokinase is found in the liver glucose metabolism (2)(3). This distinction between these two enzymes is due to the storage of glycogen in both locations.

What is phosphorylation?
Phosphorylation is simply adding a phosphate to an organic substance. In this case, a phosphate is added to the 6th carbon of the glucose molecule, and this is the reason for the name Glucose-6-Phosphate.

What is Adenosine Tri-Phosphate (ATP)?
Adenosine Tri-Phosphate is our most basic source of energy and is used in countless processes within the body. This molecule is most important due to its three phosphates (Tri-Phosphate) rendering it high in potential energy if a phosphate is taken off (as is done in this step)(5).

 

                                                        Step 2: Glucose-6-Phosphate --> Glucose-1-Phosphate

So, the body has metabolized the glucose molecule in its first step to Glucose-6-Phosphate and now needs to convert it to yet another structure called Glucose-1-Phosphate. It does this as an intermediary step between Glucose-6-Phosphate and the following step to this one (6). This is all accomplished with the attachment of Phosphoglucomutase which “anchors” on Glucose-6-Phosphate giving a phosphate at a different point on the molecule now creating an intermediary molecule called Glucose-1,6-Biphosphate by phosphorylating the 1 and 6 position of the glucose molecule, effectively dephosphorylating the enzyme itself which is then re-phosphorylated at location 6, leaving only location 1 phosphorylated and as a result creating Glucose-1-Phosphate with a re-phosphorylated enzyme (7).

What is Phosphoglucomutase?
Phosphoglucomutase is the enzyme that phosphorylates and de-phosphorylates Glucose-1,6-Phosphate.

What is Glucose-1,6-Biphosphate?
This is an intermediary molecule that acts as a “holder” of phosphate until Phosphoglucomutase can reorient and de-phosphorylate position 1 or position 6 on the glucose molecule (in this instance, it de-phosphorylates position 6 to leave position 1 phosphorylated and change the structure of the glucose molecule in preparation for the next synthesis step).

 

                      Step 3: Uridine Tri-Phosphate attaches to Glucose-1-Phosphate --> Uridine Di-Phosphate Glucose

Now we have Glucose-1-Phosphate, yet the body does not store Glucose-1-Phosphate to create glycogen, because Glucose-1-Phosphate is in a state more likely to be catabolized than added to glycogen due to its low energy yield (9). So, the cell must find a way to increase the energy yield of the current glucose molecule (Glucose-1-Phosphate) and does so with the introduction of Uridine Triphosphate (UTP). As with all these reactions, UTP does not just bump into glucose-1-phosphate accidentally, but is put together by UDP-Glucose Pyrophosphorylase (6)(9). With this combination of UTP and Glucose-1-Phosphate via the enzyme UDP-Glucose Pyrophosphorylase, a more energetically desirable product is formed in Uridine Diphosphate Glucose with a leftover di-phosphate (also known as pyrophosphate)(6)(9).


 

What is UDP-Glucose Pyrophosphorylase?
Yet another enzyme in the process of glycogenesis; this enzyme attaches a phosphate and uridine to Glucose-1-Phosphate to create Uridine Di-Phosphate Glucose (10).

Why is it called Uridine Diphosphate Glucose?
I would imagine that the name stems from having a newly added uridine, its accompanying phosphate added to the already existing phosphate found on Glucose-1-Phosphate (as explained in step 2).

What is Uridine Triphosphate (UTP)?
Uridine stemming from the nucleic base of RNA called Uricil (remember Adenine, Cytosine, Guanine, and Uricil from biology class?) with three phosphates as seen in the previous Adenosine Triphosphate from step 1. However, in this case, UTP acts as an activator of glucose to render it capable of storage by the cells as glycogen.

 

                                                        Step 4: Glycogenin priming Uridine Diphosphate Glucose

Here we finally have an activated glucose molecule (Uridine Diphosphate Glucose) meaning the cell has an energetically worthwhile glucose to store as glycogen. However, there is yet another necessity. This necessity comes in the form of a primer by creating a small piece of glycogen on which to stack our activated glucose to lengthen the branches of glycogen (6). Essentially, the cell needs foundation pieces to each of its glycogen chains, like the base of a tree. So, Glycogenin is used to only build the base of the glycogen chain. Using Uridine Diphosphate Glucose, Glycogenin creates a foundation piece with which the next enzyme I will discuss can add upon, making a full glycogen branch of glucose residues (6)(11).

 

Glycogenin

Glycogen branches

What do we mean by “activated” glucose?
Glucose that first enters the cell for glycolysis is not in a state to be stored. Structurally, it does not fit into the glycogen system, because it must go through several processes (as we have seen through each step) to change its structure (phosphorylation, addition of uridine) to be energetically viable and, arguably, "tagged" by the UDP for synthesis of glycogen.

What is a primer?
A primer is simply something that can make the foundation a reality. In this case, glycogenin is that primer. Glycogenin uses 7 alpha 1g4 glycosidic bonds (discussed shortly) to build the 8 glucose residue primer for further glycogen synthesis (11).

What is Glycogenin?
There is more than just one enzyme that acts in the actual synthesis of glycogen from activated glucose, this is the enzyme that acts to prime/start/create the foundation for the lengthening of branches that will be added on by the subsequent enzymes (6)(12).


                                                          Step 5: Uridine Diphosphate Glucose --> Glycogen

So, we have a primed glycogen molecule, we have more activated glucose in the form of Uridine Diphosphate Glucose at our disposal, and now two enzymes work together to pull it all together into full glycogen. These two enzymes are necessary, because of two different bonds used in building glycogen; for clarity, let’s examine each based on their bond.


a 1g4 glycosidic bond (Glycogen Synthase)

The enzyme Glycogen Synthase takes Uridine Diphosphate Glucose and attaches it to glycogen via a particular bond called an alpha 1g4 glycosidic bond, linking the 1 carbon of the activated glucose to the 4 carbon of the glycogen. Glycogen Synthase does not attach Uridine Diphosphate Glucose to a glycogen chain without a primer, however, so this all occurs after a primer has been set by the previously mentioned Glycogenin, which also uses alpha 1g4 glycosidic bonds (11). The Uridine Diphosphate is released upon bonding (13).


 

Glycogen branches

a 1g6 glycosidic bond (Branching Enzyme)

So, the primer is set by Glycogenin, Glycogen Synthase has extended the glycogen chain by adding more activated glucose to said chain, but the chain cannot grow forever. So, an enzyme by the name of Amylo-(1,4 to 1,6)-Transglycosylase (Branching Enzyme) takes over. Branching Enzyme takes a set of activated glucoses attached by the a 1g4 glycosidic bonds (at this point considered glycogen) and breaks said bond at one point, pulling the glycogen chain down and starting a branch with said glycogen off the main glycogen chain using alpha 1g6 glycosidic bonds to reattach this small glycogen branch back to the main glycogen chain at the 6th carbon location of glycogen (11).

 

Branching Enzyme, however, follows certain rules so as to make the process efficient, here are those rules (11):

1. Branching Enzyme only takes 7 glucose residues (activated glucoses) from the main glycogen chain.
2. Branching Enzyme only takes from the main glycogen chain when there are at least 11 glucose residues put together.
3. The new branch must be 4 residues away from the last branch.

 

Rule #2

Rule #1

Rule #3

A reword/recap of Step 5:
This stuff can get a bit confusing, so I will explain it a different way here. Imagine a tree.

At the base of a tree are roots, and in this instance the roots are the primer catalyzed by Glycogenin. The roots start the process so the rest of the tree can grow. Once there are enough roots, the trunk comes into its own by way of activated glucose chained together by alpha 1g4 glycosidic bonds catalyzed by Glycogen Synthase. Now, we have the trunk of the tree, but we have no branches. Branches are placed by.. you guess it, Branching Enzyme. Branching Enzyme starts building branches, but doesn’t want those branches to be too close to one another or to be too short, so it builds branches a little ways away from one another.

Now you have a rough understanding of how these several enzymes work to create glycogen.

So, now, after everything discussed, you have a detailed understanding of how the body goes from having pure glucose broken down from our nutrition to having stored activated glucose known as glycogen.


 

                                                                                                           Citations

1) Glycolysis, Krebs Cycle, and other Energy-Releasing Pathways. (n.d.). Retrieved August 14, 2015, from http://www.uic.edu/classes/bios/bios100/lecturesf04am/lect12.htm

2) Hexokinase. (n.d.). Retrieved August 14, 2015, from http://medical-dictionary.thefreedictionary.com/hexokinase


3) Glucokinase. (n.d.). Retrieved August 14, 2015, from http://medical-dictionary.thefreedictionary.com/glucokinase


4) Berg, J. (2002). Glycolysis is an Energy Conversion Pathway in Many Organisms. Biochemistry, 5th. Retrieved August 14, 2015, from http://www.ncbi.nlm.nih.gov/books/NBK22593/


5) Nave, R. (n.d.). Adenosine Triphosphate. Retrieved August 14, 2015, from http://hyperphysics.phy-astr.gsu.edu/hbase/biology/atp.html


6) Glycogenesis: How to Synthesize Glycogen. (2015, April 16). Retrieved August 14, 2015, from http://www.biochemden.com/carbohydrate-metabolism-glycogenesis/#Step_1_Glucose_Phosphorylation


(7) Najjar, V., & Pullman, M. (1954). The Occurrence of a Group Transfer Involving Enzyme (phosphoglucomutase) and Substrate. Science, 119(3097), 631-634. doi:10.1126/science.119.3097.631


(8) Britton, H. (1968). The Mechanism of the Phosphoglucomutase Reaction STUDIES ON RABBIT MUSCLE PHOSPHOGLUCOMUTASE WITH FLUX TECHNIQUES. Biochemistry Journal. Retrieved August 14, 2015, from http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1187194/pdf/biochemj00714-0006.pdf


(9) Glycogen Metabolism. (n.d.). Retrieved August 14, 2015, from http://oregonstate.edu/dept/biochem/hhmi/hhmiclasses/biochem/lectnoteskga/2kjan07lecturenotes.html


(10) Glycogen Metabolism. (n.d.). Retrieved August 14, 2015, from http://crystal.res.ku.edu/taksnotes/Biol_638/notes/chp_15.pdf


(11) Lomako, J. (2004). Glycogenin: The primer for mammalian and yeast glycogen synthesis. Biochemistry BioPhysiology Actual. Retrieved August 14, 2015, from http://www.ncbi.nlm.nih.gov/pubmed/15238248


(12) Moslemi, A. (2010). Glycogenin-1 Deficiency and Inactivated Priming of Glycogen Synthesis. The New England Journal of Medicine. doi:10.1056/NEJMoa0900661

(13) https://www.rpi.edu/dept/bcbp/molbiochem/MBWeb/mb1/part2/glycogen.htm



Illustrations:

https://en.wikipedia.org/wiki/Glucose_6-phosphate

https://en.wikipedia.org/wiki/Hexokinase

http://www.natuurlijkerwijs.com/english/glycogen_metabolism.htm

http://watcut.uwaterloo.ca/webnotes/Metabolism/glycogenSynthesisDegradation.html

http://www.biochemden.com/carbohydrate-metabolism-glycogenesis/#Step_1_Glucose_Phosphorylation

http://patient.info/education/diabetes

http://www.tutorsglobe.com/homework-help/biochemistry/glycogen-71906.aspx

Written by: Nicolas Verhoeven

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