In general terms, it is understood as a process that involves the transformation or degradation of glycogen.
However, doctors have identified that at least three cytosolic enzymes must be involved in glycogen degradation for this process to occur.
All these aspects are explained below.
What is glycogenolysis?
Glycogenolysis, or what is the same: as the decomposition of glycogen, releases glucose when necessary. In the liver, glycogen is a reserve of glucose for the maintenance of normal blood glucose levels, and its decomposition occurs mainly:
- Fasting, during the nighttime fast.
- Between meals.
- During a high-intensity physical activity.
In hepatocytes, glycogenolysis is stimulated or activated by glucagon and adrenaline, inhibited by insulin, and also subject to negative allosteric regulation by glucose.
Also, it is well known that regards muscles, glycogen is a source of energy for muscle activity; therefore, glycogen degradation occurs during contraction and only in the forces involved in the action.
In muscle cells, adrenaline stimulates glycogenolysis and regulates positive allosteric and negative effectors, AMP and calcium ions (Ca2 +), and ATP and glucose 6-phosphate, respectively.
The steps of glycogenolysis
Glycogenolysis begins with the action of glycogen phosphorylase (EC 18.104.22.168), a homodimer whose activity necessarily requires the presence of pyridoxal-5-phosphate, a derivative of pyridoxine or vitamin B6.
The enzyme catalyzes the phosphorolytic cleavage of the α- (1,4) glycosidic bond, releasing glucose molecules one at a time from the non-reducing ends, i.e., the ends with a free 4′-OH group, of the external branches. This reaction, which does not consume ATP but an orthophosphate, produces glucose 1-phosphate.
Glycogen (n glucose residues) + Pi → Glucose 1-phosphate + glycogen (n-1 glucose residues)
The following observation should be made: in the small intestine, pancreatic α-amylase (EC 22.214.171.124) catalyzes the hydrolytic cleavage of the α- (1,4) glycosidic bonds of starch and produces glucose molecules.
In vivo, glycogen phosphorylase catalyzes an irreversible phosphorolysis, a perfect reaction for the muscle in the skeletal state and the heart.
The irreversibility of the reaction is guaranteed by the ratio [Pi] / [glucose 1-phosphate], which is usually greater than 100. However, and quite the contrary, the reaction is readily reversible in vitro.
Glycogen phosphorylase acts respectively on the non-reducing ends of the branches and stops when the glucose unit that is four residues from the branch point is reached: this is the outer limit of the dextrin limit.
However, it should be borne in mind that at this point, two enzymatic activities, present in the same polypeptide chain, complete the degradation of glycogen: α- (1,4) -glucan-6-glycosyltransferase (EC 126.96.36.199) and Amylo-α- (1,6) -glucosidase or debranching enzyme (EC 188.8.131.52).
The first enzymatic activity transfers three of the four remaining glucose units of the branch to the non-reducing end of another chapter, leaving in the first chain only one glucose unit, which is linked to the chain by an α- (1,6) glycosidic link.
The second enzymatic activity hydrolyzes this α- (1,6) -glycosidic bond, releasing glucose and an unbranched chain of glucose units bound to (1,4).
Without the branch, glycogen phosphorylase can continue eliminating glucose units until it reaches the next dextrin limit.
Therefore, the products of the reactions catalyzed by the three enzymatic activities are:
- Glucose 1-phosphate (about 90% of glucose molecules released).
- A small amount of free glucose, the remaining 10% [these are the 1.6 linked residues; in muscle, the activity of hexokinase (EC 184.108.40.206) is so high that any molecule of free glucose is phosphorylated to glucose 6-phosphate and, therefore, is activated and metabolized within the cell].
- A smaller, less branched glycogen molecule.
The metabolic fate of glucose 1-phosphate in muscle and liver
Glucose 1-phosphate is a charged molecule and therefore is trapped inside the cell.
It is converted into glucose 6-phosphate in the reaction catalyzed by phosphoglucomutase (EC 220.127.116.11), the same enzyme that intervenes in glycogen synthesis by converting glucose 6-phosphate to glucose 1-phosphate.
This enzyme catalyzes a reversible reaction: the direction is determined by the relative concentrations of the two molecules, and in this case, it moves the phosphate group from C1 to C6.
Covalent regulation of glycogenolysis in muscle and liver
Cascade mechanism of adrenaline and glucagon action
The degradation of glycogen is under precise control through covalent and allosteric modifications of some essential proteins, such as phosphorylase kinase (EC 18.104.22.168), glycogen phosphorylase, and protein phosphatase 1.
Here, we analyze the effects of two hormones, which act through covalent modifications of target proteins:
- Adrenaline (also known as epinephrine ) is produced by the adrenal glands, which act, for example, on muscle, liver, and fat cells.
- Glucagon is produced by the alpha cells of the pancreas, which act on hepatocytes and adipocytes.
These hormones, which bind to their membrane receptors, trigger an identical cascade of intracellular events that amplify their signal by several orders of magnitude, stimulating glycogenolysis and inhibiting glycogen synthesis.
It should be noted that even acetylcholine, by binding to the receptor located in the neuromuscular junction, triggers the same cascade of adrenaline and glucagon activations.
Here are the proteins involved in the cascade.
The β-adrenergic receptors
The receptors for adrenaline and glucagon are integral membrane proteins with seven transmembrane α helices.
The term “adrenergic” is derived from adrenaline. There are four subtypes of adrenergic receptors: α1, α2, β1, and β2. In the discussion, only β1 and β2 receptors, called β, will be considered, acting in the same way.
The β-adrenergic receptors cause changes in energy metabolism, such as:
- An increase in the degradation of glycogen in muscle and liver cells.
- An increase in the breakdown of triglycerides ( lipolysis ) in adipose tissue.
G stimulating proteins
The binding of the hormone to the receptor causes a conformational change in the cytosolic portion of the receptor, which modifies the interaction with the second protein in the cascade: the stimulating guanine nucleotide-binding protein or, more simply, stimulating G protein (GS ).
It is a heterotrimer composed of three subunits: α (containing the nucleotide-binding site), β, and γ. In the inactive form, GSαβγ-GDP, the heterotrimer is coupled to β-adrenergic receptors.
The conformational changes in the receptor allow it to catalyze the substitution of GDP with GTP in the α subunit of the GSαβγ complex.
This leads to the dissociation of the trimer in an inactive dimer, βγ, and the GSα-GTP complex that moves along the plane of the inner surface of the plasma membrane, to which it is anchored by a palmitoyl group covalently linked, up to that reaches adenylyl cyclase (EC 22.214.171.124).
Note: the action of GS resembles that of Ras proteins, another class of G proteins involved in the transduction of insulin signals.
It is an integral membrane enzyme whose active site is on the cytosolic side of the plasma membrane. The interaction between GSα and adenyl cyclase activates the enzyme, which, in turn, catalyzes the synthesis of cAMP of ATP. This leads to an increase in the intracellular concentration of the cyclic nucleotide.
The stimulating activity of GSα is self-limited since it is a GPTasi; that is, it hydrolyzes the GTP bound to the GDP, turning itself off. In the inactive form, GSα is dissociated from adenyl cyclase and annealed with the Gβγ dimer. Therefore, the heterotrimer is again available to interact with a hormone-receptor complex.
Protein kinase A
The cAMP binds and activates the protein kinase-dependent on cAMP or protein kinase A or PKA (EC 126.96.36.199). The inactive form of the enzyme is a tetramer composed of two catalytic subunits and two regulatory subunits.
Each of the two regulatory subunits has an autoinhibitory domain; this means, in general terms, a region that occupies the binding site for the substrate of each catalytic subunit.
The binding of two molecules of cAMP to two sites in each regulatory subunit leads to a conformational change or transformation that causes and causes its dissociation from the tetramer, thus releasing the two catalytic subunits as active enzymes.
The active form of PKA catalyzes the phosphorylation of some proteins, activating or inhibiting them, such as:
- Glycogen synthase (EC 188.8.131.52), inhibited.
- Hormone-sensitive lipase (EC 184.108.40.206), activated.
- Phosphofructokinase 2 / fructose-2,6-bisphosphatase (EC 220.127.116.11 and EC 18.104.22.168 respectively), activated.
- Inhibitor-1 and the glycogen binding subunit (G) of the protein phosphatase one were activated.
- Phosphorylase kinase activated.
CAMP has a short half-life: it is hydrolyzed to AMP, which has no second messenger activity, in the reaction catalyzed by the cyclic nucleotide phosphodiesterase (EC 22.214.171.124).