Diseases Associated with Glycogen Synthesis

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1 Paper : 04 Metabolism of carbohydrates Module: 29 Principal Investigator, Dr. S.K.Khare, Professor IIT Delhi. Paper Coordinator Content Writer Dr. Ramesh Kothari, Professor Dr. Vijaya Khader UGC-CAS Dr. MC Varadaraj Department of Biosciences Saurashtra University, Rajkot-5 Gujarat-INDIA Dr. Chirantan Rawal, Assistant Professor Department of Microbiology, Silvassa College. Silvassa, UT of Dadra & Nagar Haveli, Content Reviewer: Prof. S. P. Singh, Professor UGC-CAS Department of Biosciences Saurashtra University, Rajkot-5 Gujarat-INDIA 1

2 Description of Module Subject Name Paper Name Module Name/Title 04 Metabolism of carbohydrates 2

3 Diseases Associated With Glycogen Synthesis Objectives 1. To understand the concept of glycogen storage diseases (GSD). 2. To study Glycogen storage diseases associated with the glycogen synthesis. 3. To understand the molecular basis of diseases. 3

4 Introduction Glycogen storage disease (GSD) relates to a set of metabolic disorder occurs due to the defective glycogenesis or glycogenolysis. Classification of glycogen storage diseases are according to the type of enzymatic deficiency. It is also classified on the basis of kind of primary organs involved. GSDs are usually diagnosed in infants or early childhood. Enzymes associated with GSDs are involved in the regulation of glycogen metabolism. It is observed that there is phenotypic variation is observed when specific enzyme is altered by mutation. Such diseases concern primarily the liver, skeletal muscle, heart and sometimes the central nervous system and the kidneys. These distinctive diseases are relatively diverse in age of onset of symptoms, morbidity and mortality. A person with a GSD has a deficiency of one of the enzymes responsible for synthesis or degradation of glycogen in the body. It results in to abnormal concentration of glycogen in the tissue or imperfectly formed glycogen. In Glycogen storage diseases, human body is not able to make enough glucose, or not able to use glucose as a source of energy. Diagnosis of GSDs depends on an individual's symptoms. Glycogen storage diseases are genetic disorders. They are caused due to mutation in the genes related to glycogen metabolism. General diagnosis: It is detected in infancy or early childhood. In severe case it is immediately identified while milder types may not be identified or unnoticed for several years. General characteristic symptoms include hypoglycaemia, hepatomegaly (enlarged liver), growth retardation, and irregular blood biochemistry. A more specific diagnosis can be done by analysing concentration of glycogen in a biopsy sample or by assaying the sample for enzyme activity. Genetic diagnostic techniques are also available. GSD's are currently not curable. Generally it is treated to manage symptoms. Treatment involves organ transplants or dietary treatment. In future, It may be possible to treat such diseases by using gene therapy In this chapter, we will learn GSDs associated with Glycogen Synthesis. 4

5 Overview of Glycogen synthesis Glycogenesis and glycogenolysis occur by different pathways. Glycogen synthesis involves the use of an activated form of glucose. Mammals, fungi and eukaryotic heterotrophic microorganisms use UDP-Glucose while bacteria and photosynthetic eukaryotes use ADP-Glucose. Initially glucose is phosphorylated to glucose 6-phosphate. This reaction is catalyzed by hexokinase (muscle) or glucokinase ( liver). Phosphoglucomutase catalyse the isomerisation of Glucose 6-phosphate to glucose 1- phosphate. Now UDP-glucose pyrophosphorylase catalyse the formation of UDP-glucose from UTP and glucose 1-phosphate. Glycogen synthase transfers the glucosyl residue from UDP-glucose to the non reducing terminal residues of glycogen. It is transferred to hydroxyl terminal of C4 end of glycogen to form an α-1 4 glycosidic bond. UDP-glucose + (glycogen) n residues UDP + (glycogen) n+1 residues Glycogen synthase catalyzes only α- 1 4 glycosidic bonds. It results in to the formation of α- amylose. Branching is catalysed by separate enzyme called Branching enzyme. It is also known as amylo-( ) transglycosylase. Students may refer module 25 (glycogenesis) for further details. 5

6 Hexokinase GLUCOSE GLUCOSE-6-PHOSPHATE ATP ADP Phosphoglucomutase UDP-glucose pyrophosphorylase GLUCOSE-1-PHOSPHATE UDP-GLUCOSE UTP 2PPi Glycogen synthase GLUCOSE+ GLUCOSE +.. Leads to formation of glycogen Fig: 29.1 OVERVIEW OF GLYCOGENESIS 6

7 Glycogen Storage Disease O Glycogen Storage Disease Type IV 7

8 Glycogen Storage Disease Type 0 It is also known as Hepatic Glycogen Synthase Deficiency It is caused due to deficiency of glycogen synthase enzyme. Glycogen synthase transfers the glucosyl residue from UDP-glucose to the non reducing terminal residues of glycogen. It is transferred to hydroxyl terminal of C4 end of glycogen to form an α-1 4 glycosidic bond. This reaction is catalysed by glycogen synthase. Glycogen synthase is the regulatory enzyme in synthesis of glycogen. Liver glycogen storage will not be there due to deficiency of glycogen synthase Carbohydrate will be converted in to lactate instead of the glycogen. This is autosomal recessive disorder. General symptoms: o Postprandial period: Hyperglycemia, glycosuria and hyperlactic acidemia after postprandial period. o Fasting: hypoglycemia and hyperketonemia o In this disease objective is to prevent the low blood sugar by evade fasting. Repeated food should be given every 3-4 hours during the day. o High protein food may help in reducing muscular cramping, tiredness, and fatigue that patient experience GLYCOGEN STORAGE DISEASE TYPE 0 Deficient Glycogen Synthase enzyme Chromosomal 12p12.2 location Diagnosis Genetic studies Quantitative analysis of glycogen synthase enzyme and glycogen Treatment Dietary treatment Gene therapy may be possible in future. 8

9 Glycogen Storage Disease Type IV It is also known as Andersen Disease, Brancher Deficiency; Amylopectinosis, Glycogen Branching Enzyme Deficiency. This is autosomal recessive disorder. It occurs due to deficiency of branching enzyme. It is also known as amylo-( ) transglycosylase After a number of glucose units have been linked as a straight chain with α1 4 linkages, branching enzyme breaks α 1 4 bonds. It breaks a 7 unit segment of α 1 4 residues from a glycogen chain and transfers to a C-6 hydroxyl group of a glucosyl residue that is four residues away from an existing branch. Reattachment is done by creating an α1 6 bond. In such cases branches will not form in the structure of glycogen. It will resembles amylopectin like structures. It is called PAS i.e. positive amylopectin like structures. In type IV diseases PAS will accumulate in the liver, muscles, leucocytes etc. GLYCOGEN STORAGE DISEASE TYPE IV Deficient Glycogen Branching enzyme enzyme Chromosomal 3p12 location Diagnosis Genetic studies Histological and ultra structure examination of tissue sample. Treatment Liver transplantation Gene therapy may be possible in future. 9

10 GLYCOGEN STORAGE DISEASES (Excluding disease associated with glycogen synthesis and degradation) Type VII Tarui s disease (Deficiency of phosphofructokinase in muscle and erythrocytes) It is a genetic disorder It is directly related to impairment in the glycolysis. In this disease patient is unable to breakdown glycogen in muscle cells.it result in to the interference in the functioning of muscle cells. Four types of GSD Type VII is observed The classical form is the most common form. Its symptoms observed in childhood. It is characterised by muscle pain and cramps after moderate exercise. Exercise results in to the breakdown of muscles. It releases the protein called myoglobin. It results in to the myoglobinuria. If untreated, myoglobinuria can harm the kidneys and lead to kidney failure. It is observed due to mutation in the gene of M subunit of the Phosphofructokinase enzyme. PFKM. This gene helps in the synthesis of phosphofructokinase. PFK phosphorylates fructose- 6-phosphate preceding to its cleavage into glyceraldehyde-3-phosphate which enters the energy generation phase of glycolysis.. GLYCOGEN STORAGE DISEASE TYPE VII Deficient phosphofructokinase enzyme enzyme Genetic basis Mutations in the PFKM gene results in to the type VII glycogen storage diseases. Diagnosis Genetic studies Muscle biopsy Quantitative analysis of Phosphofructokinase enzyme Treatment Dietary treatment Gene therapy may be possible in future 10

11 Glycogen Storage Disease Type XII (Aldolase A Deficiency, Glycogenosis Type 12, red cell Aldolase deficiency) It is a genetic disorder It is an autosomal recessive disorder It results due to deficiency of Aldolase A enzyme. It is caused due to homozygous mutation in the ALDOA gene. ALDOA gene encodes fructose-1,6-bisphosphate Aldolase A Aldolase A catalyses the aldol reaction. This reaction is reversible. It act on the fructose 1,6-bisphosphate (F-1,6-BP). Fructose 1,6-bisphosphate is split to into glyceraldehydes 3-phosphate and dihydroxyacetone phosphate (DHAP). This reaction observed in the glycolysis. Symptoms: Exercise intolerance and cramps Aldolase exist in three isoforms i.e. Aldolase A, Aldolase B and Aldolase C. Aldolase A is predominately found in the skeletal muscles and erythrocytes. Kishi et al. (1987) reported the mutation in the ALDOA gene (asp128-to-gly) while Kreuder et al. (1996) identified a homozygous mutation in the ALDOA gene ( glutamic acid to lysine ) GLYCOGEN STORAGE DISEASE TYPE XII Deficient aldolase A deficiency enzyme Chromosomal 16p11 location Diagnosis Genetic studies Muscle biopsy Quantitative analysis Treatment Gene therapy may be possible in future. 11

12 Concluding remarks The glycogen storage diseases (GSDs) and related diseases are observed due to defects of glycogenolysis, glycolysis and, glycogenesis. It is also called glycogenoses. 12