Journal of Medicinal Plants Research Vol. 5(20), pp. 4980-4983, 30 September, 2011 Available online at http://www.academicjournals.

org/JMPR ISSN 1996-0875 2011 Academic Journals

Review

Glycogen metabolism and glycogen storage diseases: A review

M. Akram1*, H. M. Asif2, N. Akhtar2, P. A. Shah3, M. Uzair4, G. Shaheen2, T. Shamim2, S. M. A. Shah2 and K. Ahmad2
1 2

Department of Basic Medical Sciences, Faculty of Eastern Medicine, Hamdard University Karachi, Pakistan. College of Conventional Medicine, Faculty of Pharmacy and Alternative Medicine, The Islamia University of Bahawalpur, Pakistan. 3 University College of Pharmacy, Punjab University Lahore, Pakistan. 4 Faculty of Pharmacy, Bahauddin Zakariya University Multan, Pakistan.
Accepted 23 June, 2011

Glycogen represents the principal storage form of carbohydrate in the mammalian body, present mainly in the liver and muscle. Liver glycogen serves as an immediate source for maintaining blood glucose levels, particularly between the meals. The glycogen stores in the liver get depleted after 12 to 18 h of fasting. Muscle glycogen is primarily concerned with the supply of hexoses that undergo glycolysis to provide energy during muscle contraction. Glycogen storage diseases characterized by deposition of normal or abnormal type of glycogen in one or more tissues result in muscular weakness, or even death. In this article, description of glycogen, glycogenesis, glycogenolysis, regulation of glycogen metabolism, glycogen storage diseases has been given. Key words: Glycogen, glycogenesis, glycogenolysis, glycogen storage diseases. INTRODUCTION Glycogen is a molecule that functions as the secondary long-term energy storage in animal and fungal cells, with the primary energy stores being held in adipose tissue. Glycogen is made primarily by the liver and the muscles, but can also be made by glycogenesis within the brain and stomach (William et al., 2006; Saladin et al., 2007). Glycogen is the storage form of glucose in animals, as is starch in plants. It is stored mostly in liver (6 to 8%) and muscle (1 to 2%), due to more muscle mass, the quantity of glycogen in muscle (260 g) is about three times higher than that in the liver (75 g). glycogen is stored as granules in the cytosol, where most of the enzymes of glycogen synthesis and breakdown are present (Geddes, 1986). Glycogen forms an energy reserve that can be quickly mobilized to meet a sudden need for glucose, but one that is less compact than the energy reserves of triglycerides (lipids) (Campbell, 2006). Only the glycogen stored in the liver can be made accessible to other organs. In the muscles, glycogen is found in a low concentration (one to two percent of the muscle mass). However, the amount of glycogen stored in the body especially within the muscles, liver, and red blood cells (Moses et al., 1972; Miwa et al., 2002; Campbell, 2006) mostly depends on physical training, basal metabolic rate, and eating habits such as intermittent fasting. Small amounts of glycogen are found in the kidneys, and even smaller amounts in certain glial cells in the brain and white blood cells. The uterus also stores glycogen during pregnancy to nourish the embryo (Miwa et al., 2002). FUNCTIONS OF GLYCOGEN The prime function of liver glycogen is to maintain the blood glucose levels particularly between meals. Liver glycogen stores increase in well-fed states which are depleted during fasting. Muscle glycogen serves as a fuel reserve for the supply of adenosine triphosphate (ATP) during muscle contraction (Cohen, 1985). Regulation of liver glycogen
*Correspondence author. E-mail: makram_0451@yahoo.com. Tel: 92-021-6440083. Fax: 92-021-6440079.

As a meal containing carbohydrates is eaten and

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digested, blood glucose levels rise, and the pancreas secretes insulin. Glucose from the portal vein enters liver cells (hepatocytes). Insulin acts on the hepatocytes to stimulate the action of several enzymes, including glycogen synthase. Glucose molecules are added to the chains of glycogen as long as both insulin and glucose remain plentiful. In this postprandial or "fed" state, the liver takes in more glucose from the blood than it releases. In fasting or starvation, glycogen synthesis stops and glycogen is broken down and converted to glucose. Glycogen phosphorylase is the primary enzyme of glycogen breakdown. Glucagon is secreted by the pancreas and its cause glycogenolysis and inhibits glycogenesis (Exton, 1981). In muscle and other cells Muscle glycogen does not maintain blood glucose level due to deficiency of glucose 6 phosphatase. In contrast, liver glycogen maintains blood glucose level (Pedersen et al., 2008). Glycogenesis Site: Cytosol Tissue concerned: Liver and skeletal muscle. Substrate: Glucose. Product: Glycogen. Definition: It is a pathway whereby glycogen (animal starch) is synthesized. Glycogen synthesis Glycogen synthesis is, unlike its breakdown, endergonic. This means that glycogen synthesis requires the input of energy. Glucose is phosphorylated to glucose-6phosphate by hexokinase in skeletal muscle and by glucokinase in liver. Synthesis of UDP glucose Glucose 6- phosphate is converted to glucose-1phosphate by phosphoglucomutase (glucose-1, 6bisphosphate is an intermediate). Glucose 1-phosphate reacts with uridine triphosphate (UTP) to form active nucleotide uridine diphosphate glucose (UDP-glucose) liberating inorganic pyrophosphate (ppi). This step is catalyzed by UDP glucose pyrophosphorylase hydrolysis of ppi by phrophosphatase takes the reaction to completion. Requirement of primer to initiate glucogenesis A fragment of pre-existing glycogen must act as a primer

to initiate glycogen synthesis. It is recently found that in the absence of glycogen primer a specific protein-namely glycogenin can accept glucose from UDPG. The hydroxyl group of the amino acid tyrosine of glycogenin is the site at which the initial glucose unit is attached. The enzyme glycogen initiator synthase transfers the first molecule of glucose to Glycogenin. Then glycogenin itself takes up a few glucose residues to form a fragment of primer which serves as an acceptor for the rest of the glucose molecules (Ercan et al., 1994). Branching mechanism Glycogen is synthesized from monomers of UDP-glucose by the enzyme glycogen synthase, which progressively lengthens the glycogen chain with (14) bonded glucose. As glycogen synthase can lengthen only an existing chain, the protein glycogenin is needed to initiate the synthesis of glycogen. When the chain has lengthened to a minimum of 11 glucose residue; branching enzyme also known as amylo [1-4]. [1-6] transglucosidase, transfers a chain of 5 to 8 glycosyl residues from the non reducing end of the glycogen chain (breaking an -(1-4) glycosidic bond) to another residue on the chain, where it attaches the two sections by an 1-6 linkage. The resulting non reducing end as well as the old non reducing end (from which 5 to 8 residues were removed) can be further elongated by glycogen synthase. After further elongation of these two ends has occurred, their glycosyl residues can be removed and utilized to make further branches resulting in branched, tree like, glycogen structure. Branching mechanism forms glycogen consolidated and compact due to which total body glycogen give 600 kcals even after glycogen can give only 40 kcals in 70 kg man). Rate of glycogen synthesis and degradation increases due to increasing the sites (non reducing ends) for actions of glycogen phosphorylase and glycogen synthase. The glycogen molecule becomes soluble. Glycogenolysis Action of glycogen phosphorylase The degradation of stored glycogen in liver and muscle constitutes glycogenolysis. The 1, 4- glycosidic bonds (from the non-reducing ends) are cleared sequentially by the enzyme glycogen phosphorylase to yield glucose 1phosphate. This process called phosphorrolysis continues until four glucose residues remain on either side of branching point (1, 6-glycosidic link). The glycogen so formed is known as limit dextrin which cannot be further degraded by phosphorylase. Glycogen phosphorylase possesses a molecule of pyridoxal phosphate, covalently bond to the enzyme (Villar, 1994)

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Table 1. Glycogen storage diseases (Scriver, 1995).

Type Type I Von disease Gierkes

Defective enzyme Deficiency of glucose phosphatase Lysosomal glucosidase Debranching enzyme Branching enzyme

Clinical features Liver cells and renal tubule cells loaded with glycogen, hypoglycemia, lacticacidemia, ketosis, hyperlipidemia. Fatal, accumulation of glycogen in lysosomes, heart failure. Accumulation of a characteristic branched polysaccharide. Accumulation of a polysaccharide having few branch points. Death due to cardiac or liver failure in first year of life.

Type II Type III Type IV

Pomps disease Coris disease Anderson disease

alpha

Type V

Mc Ardles syndrome

Skeletal muscle phosphorylase Liver phosphorylase

glycogen

Diminished exercise tolerance; muscles have abnormally high glycogen content (2.5 to 4.1%). Little or no lactate in blood after exercise. High glycogen hypoglycemia. content in liver, tendency towards

Type VI

Hers s diseases

glycogen

Type VII

Taruis disease

Phosphofructokinase

Diminished exercise tolerance; muscles have abnormally high glycogen content (2.5 to 4.1%). Little or no lactate in blood after exercise. Hemolytic anemia. High glycogen hypoglycemia. content in liver, tendency towards

Type VIII

Sex linked

Phosphorylase kinase

Action of debranching enzyme The branches of glycogen are cleared by two enzyme activities present on a single polypeptide called debranching enzyme hence it is a bifunctional enzyme. Glycosyl 4; 4 transferase (Oligo,1-4, 1-4 glucan transferase) activity removes a fragment of three of four glucose residues attached at a branch and transfers them to another chain. Here, one 1-4 bond is cleaved and the 1-4 bond is made but the places are different. Amylo 1-6glucosidase breaks the 1-6 bond at the branch with a single glucose residue and releases a free glucose. The remaining molecule of glycogen is again available for the action of phosphorylase and debranching enzyme to repeat the reaction (Cohen, 1983). Formation of glucose 6-phosphate and glucose Through the combined action of glycogen phosphorylase and debranching enzyme glucose 1-phosphate and free glucose in a ratio of 8 are produced. Glucose 1phosphate is converted to glucose 6-phosphate by the enzyme phosphoglucomutase. Fate of glucose 6-phophate The fate of glucose 6-phophate depends on the tissue.

The liver, kidney and intestine contain the enzyme glucose 6-phosphatase that cleaves glucose 6-phosphate to glucose. This enzyme is absent in muscle and brain hence free glucose cannot be produced from glucose 6phosphate in these tissues. Therefore, liver is the major glycogen storage organ to provide glucose into the circulation to be utilized by various tissues. In the peripheral tissues glucose 6-phosphate produced by glycogenolysis will be used for glycolysis. It may be noted that though glucose 6-phosphatase is absent in muscle some amount of free glucose (8 to10% of glycogen) is produced in glycogenolysis due to the action of debranching enzyme (1-6 glucosidase activity). Glycogen storage diseases Inherited deficiencies in specific enzymes of glycogen synthesis or breakdown in both liver and muscle are the causes of glycogen storage diseases. Glycogen storage diseases are given in Table 1 (Randle et al., 1981). DISCUSSION Glycogen is the major storage form of carbohydrates in animals and corresponds to starch in plants. It occurs mainly in liver (upto 6%) and muscle, where it rarely exceeds 1%. However, because of its greater mass,

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muscle represents some three to four times as much glycogen store as liver. It is present in high concentration in liver, followed by muscle, brain etc. glycogen is also found in plants that do not possess chlorophyll (e.g. yeast, fungi). The structure of glycogen is similar to that of amlyopectin with more number of branches. Glycogen can be rapidly mobilized. Glycogen can generate energy in the absence of oxygen. Brain depends on continuous glucose supply which mostly comes from glycogen. Glycogen synthase is responsible for the formation of 1, 4- glycosidic linkages. This enzyme transfers the glucose from UDP-glucose to the non-reducing end of glycogen to form 1-4 linkages. Glycogen however, is a branched tree-like structure. The formation of branches is brought about by the action of a branching enzyme namely glucosyl 4-6 transferase (Amylo 1-4, 1-6 transglucosidase). This enzyme transfers a small fragment of five to eight glucose residues from the non-reducing end of glycogen chain (by breaking 1-4 linkages) to another glucose residue where it is linked by 1-6 bond. This leads to the formation of a new nonreducing end, besides the existing one. Glycogen is further elongated and branched, respectively by the enzymes glycogen synthase and glucosyl 4-6 transferase. The overall reaction of the glycogen synthesis for the addition of each glucose residue is of the two ATP, of which one is required for the phosphorylation of glucose, while the other is needed for conversion of UDP to UTP. Pathway of glycogenesis requires a primer. Primer may be a glycogen fragment of a pre-existing molecule, a protein containing an oligosaccharide of a (1, 4)-glucose units, attached to the phenolic oxygen atom of tyrosine residue, a specific protein in which the OH group of serine and threonine side chains serve as acceptor sites. The growing chain accepts the glucose residues through (1-4) linkages at the non-reducing ends liberating UDP in presence of glycogen synthase (Raz et al., 1991). Glycogen storage disease is a generic term intended to describe a group of inherited disorders characterized by deposition of an abnormal type or quantity of glycogen in the tissues. CONCLUSION Glycogen is synthesized from glucose and other precursor by the pathway of glycogenesis. It is broken down by a separate pathway known as glycogenolysis.

Glycogenolysis leads to glucose formation in liver and lactate formation in muscle owing to the respective presence or absence of glucose 6 phosphatase. Glycogen storage disease is a generic group of disorders that result from defect in steps of glycogen synthesis or glycogen degradation. These are characterized by deposition of an abnormal type of quantity of glycogen in a single tissue like liver or may be more generalized, affecting the muscle, kidney, intestine and myocardium. Severity of the disease may range from fatal in infancy to mild disorders which are not life threatening (Selby, 1991).
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