Glycogen Branching Enzyme 1

So we've talked a quite a bit about the GBE1 gene, where a missense mutation, that lead to the replacement of a tyrosine (tyr) amino acid with a serine (ser) amino acid (it's case specific), an amino acid with hydrophobic side chain, with a polar, uncharged side chain, gives a non-functional GBE protein. And this is the cause of all our problems in Andersen's Disease. So, let us understand a bit more about the Glycogen Branching Enzyme.

So you ate this. Ice-cream. You ate 3 tubs all by yourself for lunch at 12 noon and your blood glucose concentration rises as a result of the "meal". The blood also enters the beta cells of the Islets of Langerhans in the pancreas, and the glucose diffuses into the beta cell via vesicles. In the cell, the following biochemical reaction occurs:

Flashback to glycolysis chapter

G6P is subsequently oxidised to form ATP. The presence of ATP causes potassium ion channels to close for depolarization of the cell membrane to occur. Voltage-gated calcium channels open, for an influx of Ca2+ ions. This stimulates the release of insulin. Insulin will stimulate the action of several enzymes by binding to the insulin receptor for a cascade of reactions to occur.

An active form of glucose, UDP-glucose is formed through the formation of alpha-1-4 glycosidic bond, to give a linear glycogen chain. (Note UDP, Uridine triphosphate is similar to ATP, just more specific) This all occurs normally, even with a mutation in the GBE1 gene. It is in the second step of the production of branched glycogen where the issue begins.

The branching of glycogen requires a branching enzyme for the formation of an alpha-1,6 linkage between the core and the branch of around 6 residues. This will give rise to the formation of a branched glycogen. And as such, you can be a happy child and eat more ice-cream! (Please note, that pink-brown thing is supposed to be an ice-cream cone - I tried).

Thus, GBE is need since its involved in carbohydrate metabolism by it catalysing the transfer of a segment of a (1-->4)-alpha-D-glucan chain to a primary hydroxyl group in a similar glucan chain during glycogenesis. It acts on linear glycogen chains produced when UDP-glucose is synthesized through the formation of alpha-1-4 glycosidic bond. In humans, glycogen is the alpha glucan produced during glycogenesis.

Let's take note of something important here first:

Amylopectin

- Has both alpha-1-4 glycosidic bond & alpha-1,6 linkage

- Has less branching (branches are separated by 12-20 glucose units)

Glycogen

- Has both alpha-1-4 glycosidic bond & alpha-1,6 linkage

- Has MORE branching (interval of 8-10 glucose units)

- Thus, more glucose units present

 Alternate names of GBE:

- amylo-(1,4 to 1,6) transglucosidase

- branching enzyme 

- glycogen branching enzyme

- 1,4-alpha-glucan branching enzyme

Enzyme Commission (EC) Number: 2.4.1.18 (ExPASy)

Q04446 (UniPro/SwissProt)

Thus, without GBE / with a dysfunctional GBE, branched glycogen (polyglucosan bodies) may be created in a manner where it resembles amylopectin. Amylopectin-like polyglucosan bodies can be broken down by a type of amylase, however, the enzymes that are synthesized for glycogenolysis (the breaking down of glycogen) are just glycogen phosphorylase and the debranching enzyme. 

Insufficient research coupled with technological limitations has left its most of the molecular mechanism of GSD IV unknown and currently, incurable.

As such, the synthesised glycogen is unable to be degraded via proteolytic cleavage to give glucose. This leads to the:

- Accumulation of amylopectin-like polyglucosan bodies

- No glycogenolysis to get glucose

- No ice-cream for you

:(