glycogenolysis

Glycogenolysis, 

process by which glycogen, the primary carbohydrate stored in the liver and muscle cells of animals, is broken down into glucose to provide immediate energy and to maintain blood glucose levels during fasting. Glycogenolysis occurs primarily in the liver and is stimulated by the hormones glucagon and epinephrine (adrenaline).

enzyme defects affecting glycogen breakdown in muscle

glycogenolysis are:

1.

Glycogen phosphorolysis. Glycogen degradation is initiated by the action of phosphorylase, a serine–threonine kinase which catalyzes the rupture of α1→4 glycosidic bonds by insertion of a phosphate at carbon 1. The phosphate employed in this reaction is obtained from the medium (Pi) and the hydrolysis of ATP is not necessary. Phosphorylase acts on the nonreducing ends of glycogen branches, releasing glucose-1-phosphate. Its action stops four glucose residues before an α1→6 junction (Fig. 14.3). At this point, another enzyme, oligo-α(1,4)-α(1,4)-glucantransferase, separates a trisaccharide from the terminal branch and transfers it to the end of a neighbor branch, where it is attached via a α1→4 bond. The branch is reduced to a single glucose with an α1→6 bond.

Phosphorylase contains pyridoxal phosphate covalently bound to it, which serves as an essential cofactor that promotes the hydrolysis of the glycosidic bond. It is an important regulatory enzyme of the pathway that responds to allosteric effectors and to phosphorylation–dephosphorylation modifications. Chapter 19 will expand on this topic.

2.

Hydrolysis of α1→6 glycosidic bonds. This is catalyzed by α1→6-glucosidase, or debranching enzyme, which releases free glucose. The α1→6 glucosidase and oligo-α(1,4)→α(1,4)-glucantransferase activities depend on the action of a single protein with two active sites of different specificity. After the action of the debranching enzyme, phosphorylase continues releasing glucose-1-P until the enzyme reaches a distance that is four glucose molecules apart from the next α1→6 bond. At this point, the hydrolysis of α1→6 bonds is catalyzed by the enzymes mentioned previously. The concerted action of phosphorylase, oligo-α(1,4)→α(1,4)-glucantransferase, and α1→6-glucosidase releases glucose-1-P and some free glucose molecules (debranching enzyme causes hydrolysis and not phosphorolysis). Only the glucose in the branching position is released as free glucose. All other molecules are released as G-1-P. On average, a free glucose molecule is produced for every nine molecules of glucose-1-P, which indicates the degree of glycogen molecule branching.

3.

G-6-P formation. Glucose-l-phosphate is converted into G-6-P by phosphoglucomutase. This is the reverse reaction that produces G-1-P in glycogenesis.

4.

Free glucose formation. The last stage of glycogenolysis is the hydrolysis of G-6-P to glucose and inorganic phosphate, catalyzed by G-6-P.

The reaction from glucose to G-6-P, catalyzed by glucokinase in glycogenesis, is essentially irreversible. For this reason, the reverse process is accomplished by another enzyme, G-6-phosphatase. This enzyme is found in liver and kidney cell membranes and in intestinal cell endoplasmic reticulum, but not in muscle cells. This explains why the liver, kidney, and intestine can release glucose to the circulation and muscle cannot. G-6-phosphatase is a complex with five subunits; three of them carry G-1-P and G-6-P through the ER membrane. One of the subunits belongs to the GLUT transporter family (GLUT7) and transports glucose from the ER to the cytosol.

In muscle, glycogen degradation starts with stages similar to those described earlier. However, G-6-P cannot be hydrolyzed because there is no G-6-P in muscle; thus, G-6-P continues its catabolic pathway mainly through glycolysis.

Mechanism

The key regulatory enzymes of glycogenolysis are phosphorylase kinase and glycogen phosphorylase, both activated by phosphorylation. These will predominantly express in the liver, muscle, and brain.

The process of glycogenolysis starts in the muscle due to the activity of the enzyme adenyl cyclase and cAMP. cAMP then binds to phosphorylase kinase and converts it to its active form, which then converts phosphorylase b to phosphorylase a, which finally catalyzes the breakdown of glycogen.

The process of glycogen breakdown can occur either in the cytosol or in the lysosomes. In the cytosol, the enzyme glycogen phosphorylase catalyzes the release of glucose-1-phosphate from the ends of glycogen branches with the use of inorganic phosphate to cleave α-1,4 bonds.After that, glucose-1-phosphate can convert to glucose-6-phosphate. In the lysosome, the enzyme acid α-glucosidase degrades lysosomal glycogen via an autophagy-dependent pathway. It is known that the latter process serves as an immediate source of energy in the newborn period.

Since the enzyme phosphorylase can only cleave until it is four units from a branch point, when glycogen phosphorylase reaches a branch point that is four glucose residues away, the enzyme glycogen debranching enzyme transfers one of the branches to another chain, forming a new α-1,4 bond and leaving a single glucose unit at the branch point, which is later hydrolyzed by α-1,6-glucosidase, forming free glucose.

Clinical Significance

Von Gierke disease, also known as glycogen storage disease type 1A, is an autosomal recessive disorder in which the enzyme glucose-6-phosphatase is deficient, leading to an inability to break down glycogen into glucose. It has an incidence of 1 in 100,000 live births. The clinical presentation is characteristically an infant, usually at the age of three to six months (although the age of presentation is variable), presenting with hypoglycemia and hepatomegaly, frequently accompanied by hyperlipidemia, hyperuricemia, and lactic acidosis. An enzyme assay and liver biopsy confirm the diagnosis. It is manageable through adequate dietary therapy for preventing long-term complications.

Pompe disease, also known as glycogen storage disease type II or acid maltase deficiency, is an autosomal recessive disorder resulting from mutations in the GAA gene on chromosome 17q25, coding for acid alpha-glucosidase, leading to lysosomal accumulation of glycogen in various tissues, but mostly affecting cardiac and skeletal muscles. The clinical presentation depends on the specific mutation and the resulting level of residual acid alpha-glucosidase activity. It is classified depending on the timing of presentation: classic infantile-onset Pompe disease, with an age of onset ≤ 12 months and late-onset Pompe disease, which manifesting any time after 12 months of age. The classic type characteristically demonstrates a rapidly progressive hypertrophic cardiomyopathy and left ventricular outflow obstruction, accompanied by muscle weakness, hypotonia, and respiratory distress. Motor development is delayed. The main cause of death is cardiac and respiratory failure, most commonly occurring before one year of age. The late-onset type usually lacks cardiac involvement; it presents with muscle weakness progressing to profound weakness and wasting, eventually requiring a wheelchair. Respiratory failure due to the involvement of the diaphragm is a common complication.

Cori Disease: also known as glycogen storage disease type III or limit dextrinosis, is a genetic disease caused by a mutation in the AGL gene located in the chromosome 1p21 encoding for glycogen debranching enzyme (amylo-1,6-glucosidase), leading to a deficient activity in the key enzyme responsible for glycogen degradation. The characteristic clinical presentation is hypoglycemia, hyperlipidemia, growth retardation, and hepatomegaly. It can subdivide into type IIIa, which present with hepatic and muscle involvement, that can develop myopathy and cardiomyopathy, and type IIIb, which primarily presents with liver disease

McArdle disease: also known as glycogen storage disease type V or myophosphorylase deficiency, is an autosomal recessive inborn error of skeletal muscle metabolism in which glycogen phosphorylase activity is affected, resulting in an inability to break down glycogen. It results from nonsense mutations in the PYGM-gene on chromosome 11, which codes for muscle glycogen-phosphorylase (myophosphorylase). Since muscle glycogen-derived glucose is unavailable during exercise, and glycogen is the primary fuel in exercise, exercise intolerance characterizes the clinical scenario. Vigorous exercise will often cause contractures and rhabdomyolysis accompanied by myoglobinuria.

Glycogenolysis activated by catecholamines, such as norepinephrine, has been implicated in memory consolidation.