Glycogenolysis

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, cannot be used directly by our metabolism. After its storage (glycogenesis), it must go through certain steps to then be re-released as a viable form of energy and it is in this article we will examine, step by step, the mechanism that allow our glycogen to be used by our body. Let’s dive in.

What is glycogenolysis?
Glycogenolysis is, in the simplest form, the breakdown of glycogen into a form of energy that can be readily be used by the body - glucose [1].

Where does it occur?
Glycogenolysis occurs, primarily, in the cytoplasm of the liver and muscle cells [1].

Why does it matter?
While it is important to have glucose stored in the form of glycogen when there is an abundance of glucose, it is equally important to be able to use that glycogen when there is a shortage of energy. In cases of intense exercise, for example, the body goes through glycogenolysis to meet demand with supply [1].

How does glycogenolysis occur?
Now that we understand what this all is and why this process occurs in a countless number of cells of our body, let us go ahead and examine exactly how this all occurs.

                                                             Step 1: UDP-Glucose --> Glucose-1-Phosphate
You may or may not be aware that Uridine Di-Phosphate Glucose is considered the “activated” form of glucose that allows it to be stored as a residue in a glycogen chain. If you are unaware of this fact, please read the Glycogenesis article as it is from this article’s final point that we will need to circle back through various steps. Otherwise, simply know that Uridine Di-Phosphate Glucose is used to create glycogen chains and branches. These activated forms of glucose (again, UDP-Glucose) are held together in chains by alpha 1g4 glycosidic bonds and 1g6 glycosidic bonds. The majority of the glucose residues are held together by 1g4 glycosidic bonds, yet at the intersection point between each glycogen branch and glycogen chain, there is a 1g6 glycosidic bond. This first step occurs by breaking these bonds to release glucose for enzymes to run their course. Let us examine this concept further by looking at how things occur at the site of each bond.

 

a 1g4 glycosidic bonds (Glycogen Phosphorylase)

As we know, activated glucose is stuck together by 1g4 glycosidic bonds. To break these bonds apart and free glucose to be acted upon in later metabolic steps, the enzyme Glycogen Phosphorylase cleaves the bond and phosphorylates the glucose molecule. In doing so, it creates Glucose-1-Phosphate. Glycogen Phosphorylase can only cleave bonds up to 4 residues away from the base glycogen chain – at this point, the following enzyme takes over [3].

How is Glycogen Phosphorylase able to phosphorylate glucose?

Evidently, the enzyme Glycogen Phosphorylase needs to acquire a phosphoral group from somewhere to then transfer that phosphate to glucose to create Glucose-1-Phosphate. Glycogen Phosphorylase has two states of “being” between “on”, called relaxed, and “off”, called tense [4]. When tense, the enzyme does not have a phosphate to give, but when another enzyme called Phosphorylase Kinase gives a phosphate it becomes relaxed and is now able to phosphorylate glucose. It is also possible for Glycogen Phosphorylase to be activated by a high amount of Adenosine Monophosphate (AMP indicating a low energy state of the cell) [4][5].

a 1g6 glycosidic bonds (Debranching Enzyme)

While 1g4 glycosidic bonds make up the majority of the bonds in glycogen, the base bond that attaches the many residues of glucose, that make up a glycogen branch, to a glycogen chain are held there by a 1g6 glycosidic bonds. In this case, a separate enzyme by the name of Debranching Enzyme must act upon these bonds, and for good reason – let’s examine.

      A) 4-a-D-glucanotransferase (or glucosyltranferase)

Debranching Enzyme has two distinct functions, because it has two distinctive active sites. 4-a-D-glucanotransferase, is the first of these active sites and serves as a transfer site for glucose residues. Better explained, as Debranching Enzyme comes into play once Glycogen Phosphorylase can no longer cleave and phosphorylate, this means that Debranching Enzyme begins working once Glycogen Phosphorylase reaches the last 4 glucose residues of a glycogen chain and is forced to stop; at this point, Debranching Enzyme will move the remainder of the glucose residues attached via a 1g4 glycosidic bonds (a total of 3 residues of the 4) to a different glycogen chain – it does this via the 4-a-D-glycanotransferase active site on the enzyme [2][3].

     B) Amylo a 1,6 glucosidase (or glucosidase)

Once Debranching Enzyme has moved 3 of the 4 residues to a new glycogen branch, that still leaves one residue (the “base” residue) that formerly attached all of the glucose residues, that have now been cleaved off, to the glycogen chain. This residue is held in place with an a 1g6 glycosidic bond and requires a different active site on Debranching Enzyme to break this bond. This active site is called the Amylo a 1,6 glucosidase and acts on the a 1g6 glycosidic bond by hydrolyzing the bond and the glucose molecule attached. This, then, yields in a break in the bond and a free glucose molecule [3].

 

What is the purpose of Uridine Diphosphate?

This is a question I asked myself after seeing that UDP had been the key to “activate” glucose for storage, so what was the point in having it there in the first place? Unluckily, there are few to no sources that discuss what happens or what the purpose of UDP is in terms of activating glucose. After speaking to a few professors in the physiology department at East Carolina University, the agreement was that UDP acted as a type of “tagging” system to tell glycogenesis enzymes to add the UDP-Glucose molecule to the glycogen chain, as well as making it energetically viable. Once Glycogen Phosphorylase is activated and the bonds break, UDP is discarded in some manner – how? Unsure, for the time being.
 

                                                        Step 2: Glucose-1-Phosphate --> Glucose-6-Phosphate
If you are familiar with glycogenesis, you will be pleasantly surprised by this step as it is simply a reverse reaction of the one outlined in glycogenesis. In this step, starting with the product of step 1, Glucose-1-Phosphate, the body ends up with the product Glucose-6-Phosphate. Specifically, the way the enzyme, called Phosphoglucomutase, acts on this step there is the creation of an intermediary molecule between the beginning molecule (Glucose-1-Phosphate) and the product molecule (Glucose-6-Phosphate). This intermediary molecule is called Glucose-1,6-Biphosphate. Essentially, with a phosphate already located on the first position of the glucose molecule on Glucose-1-Phosphate (hence the name Glucose-ONE-Phosphate), Phosphoglucomutase attaches and sticks a phosphate on the sixth location of the glucose molecule, as well; this, intuitively, is called Glucose 1,6 Biphosphate for having two phosphates attached to the glucose molecule. After it does this, the enzyme Phosphoglucomutase reorients itself to be able to then dephosphorylate the Glucose 1,6 Biphosphate molecule at the first position, leaving only a phosphate at the sixth location of the glucose molecule and therefor creating Glucose-6-Phosphate [3].

 

How is Phosphoglucomutase able to phosphorylate Glucose-1-Phosphate?

Phosphoglucomutase is, a bit like Glycogen Phosphorylase, phosphorylated by another enzyme called P21-activated kinase 1 [6]. It is through this phosphorylation that Phosphoglucomutase has the ability to “double” the phosphates on Glucose-1-Phosphate to create Glucose-1,6-Biphosphate. The depth of this interaction between Phosphoglucomutase and P21-activated kinase is beyond the scope of this article, however.

 

                                                      Step 3: Glucose-6-Phosphate --> Various Energy Systems
This step is highly dependent on the location it occurs. In the liver, with Glucose-6-Phosphate, the hepatic cells can either allow Glucose-6-Phosphate to be shuttled back out of the cell to then be taken up by other cells (a “redistribution” of energy), or can be moved on down the Glycolysis pathway for immediate energy [3][8]. On another note, between the two options, muscle cells are limited to only using Glucose-6-Phosphate in Glycolysis; meaning, muscle cannot release free glucose into the blood [7][8]. Another system that Glucose-6-Phosphate may be used in is the Pentose Phosphate Pathway in which it acts
 

Glycolysis

If Glucose-6-Phosphate is shuttled into Glycolysis, then an enzyme by the name of Phosphoglucose Isomerase acts on Glucose-6-Phosphate to change it to Fructose-6-Phosphate [9]. Glycolysis articles will go into this in greater depth.


 

Release Glucose

Glucose-6-Phosphate can, in the liver, be hydrolyzed to then be released as free glucose molecules into the blood stream; this serves as a way to increase blood glucose levels and transport glucose to other cells that may be in need [3][8]. An enzyme that is only present in the liver by the name Glucose-6-Phosphatase hydrolyzes Glucose-6-Phosphate leading to a product of a phosphate and a free glucose that is now able to move out of the cell’s cytoplasm into the blood [3]. Now, it does not move out of the cytoplasm without help, however. Free glucose is able to leave the cell via a transport protein called GLUT2, which, when activated, opens the channels for glucose to pass through via facilitated diffusion [10].

 

 

Pentose Phosphate Pathway

Otherwise, Glucose-6-Phosphate can also be used in the Pentose Phosphate Pathway in which it interacts with the enzyme Glucose-6-Phosphate Dehydrogenase [11]. Briefly, if unfamiliar, the Pentose Phosphate Pathway allows for the creation of NADPH which has impact on anabolic processes and aids in certain immune function [12].  



 

Writer: Nicolas Verhoeven

                                                                                                             Citations
 

[1] glycogenolysis | biochemistry | Britannica.com. (n.d.). Retrieved from http://www.britannica.com/topic/glycogenolysis

[2] 4-a-d-glucanotransferase | definition of 4-a-d-glucanotransferase by Medical dictionary. (n.d.). Retrieved from http://medical-dictionary.thefreedictionary.com/4-a-d-glucanotransferase

[3] Glycogen Metabolism. (n.d.). Retrieved from https://www.rpi.edu/dept/bcbp/molbiochem/MBWeb/mb1/part2/glycogen.htm


[4] RCSB PDB-101. (n.d.). Retrieved from http://www.rcsb.org/pdb/101/motm.do?momID=24

[5] Johnson, L. N. (1990). Glycogen Phosphorylase THE STRUCTURAL BASIS OF THE ALLOSTERIC RESPONSE AND COMPARIS. Journal of Biological Chemistry,265(6). Retrieved from http://www.jbc.org/content/265/5/2409.full.pdf


[6] Gururaj, A., Barnes, C. J., Vadlamudi, R. K., Kumar, R., & Kumar, R. (2004). Regulation of phosphoglucomutase 1 phosphorylation and activity by a signaling kinase.Oncogene. doi:10.1038/sj.onc.1207969


[7] Berg JM, Tymoczko JL, Stryer L. Biochemistry. 5th edition. New York: W H Freeman; 2002. Section 30.2, Each Organ Has a Unique Metabolic Profile. Available from: http://www.ncbi.nlm.nih.gov/books/NBK22436/

[8] lecture16. (n.d.). Retrieved from http://www.uwyo.edu/bio1000skh/lecture16.htm

[9] Phosphoglucose Isomerase. (n.d.). Retrieved from http://biology.kenyon.edu/BMB/Chime2/2001/phosphoglucose%20isomerase/FRAMES/text.htm


[10] Thorens, B., & Mueckler, M. (2010). Glucose transporters in the 21st Century.American Journal of Physiology - Endocrinology and Metabolism, 298(2), E141–E145. http://doi.org/10.1152/ajpendo.00712.2009

[11] Pentose Phosphate Pathway - Chemwiki. (n.d.). Retrieved October 4, 2015, from http://chemwiki.ucdavis.edu/Biological_Chemistry/Metabolism/Pentose_Phosphate_Pathway


[12] The physiological role of NADPH. (n.d.). Retrieved from http://watcut.uwaterloo.ca/webnotes/Metabolism/hmsNadphRole.html




 

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