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Glycogen Storage Diseases:. Overview of Glycogen Metabolism. Excess glucose stored as glycogen Glucose units joined by α -1,4 and α -1,6 glycosidic bonds Glucosyl chains are branched Fasted state (catabolic)—glycogen breakdown Fed state (anabolic)—glycogen synthesis. - PowerPoint PPT Presentation
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Glycogen Storage Diseases:
Overview of Glycogen Metabolism
• Excess glucose stored as glycogen• Glucose units joined by α-1,4 and α -1,6 glycosidic
bonds• Glucosyl chains are branched• Fasted state (catabolic)—glycogen breakdown• Fed state (anabolic)—glycogen synthesis
Anabolism – Glycogenesis
• Glycogen synthase extends chains (α-1,4) from non-reducing ends; uses UDP-glucose as substrate
• Branching enzyme (transferase function) required to form branched chains; forms α-1,6 glycosidic bonds; moves 7 residues
Anabolism – Glycogenesis
• Glycogen synthase needs to be activated for glycogenesis to occur
• Enzymes involved in breakdown need to be deactivated• Fed state dominated by insulin• Protein phosphatase I activated (also inactivates
phosphorylase kinase, not shown below)
Catabolism - Glycogenolysis
• Glycogen phosphorylase removes glucosyl unit from non-reducing end by phosphorylysis (releases glucose-1-phosphate)
• Debranching enzyme (transferase activity) moves 3 glucose units to another branch; hydrolyzes α-1,6 linkage with glucosidase function (same polypeptide chain for eukaryotes)
Catabolism - Glycogenolysis
GSD Type 0
• An inherited genetic disease• Enzyme affected: glycogen synthase• The body is unable to store glycogen• LIVER: Chromosome 12
-hypoglycemia when fasting
-hyperglycemia right after meals• MUSCLE: Chromosome 19
-frequent fatigue and muscle cramps
GSD Type 1
• Edgar von Gierke’s Disease• Most common disease type (approximately 1 in 20,000
infants)
• Characterized by:-an abnormally large abdomen due to an accumulation of glycogen in the liver-prominent hypoglycemia in between meals (may cause convulsions in infants)
Deficiency of the Enzyme glucose-6-phosphatase
• An inherited defect in chromosome 17• The body is not able to break down glycogen into glucose
Glucagon Cascade
Prolonged hypoglycemia can cause
Glucagon production
Accumulation of glucose-6-phosphate
Glycolysis
pyruvate and lactate
Fat Breakdown
Beta-oxidation
Excess acetyl CoA
Ketones
GSD Type IIPompe’s disease, acid maltase deficiency
• Alpha-1,4-glucosidase (lysosomal glucosidase; acid maltase)– Catalyzes α-1,4- and α-1,6-glucosidic linkages (hydrolysis)– Lysosomes dispose/recycle waste products
• acid alpha-glucosidase gene, mapped in
chromosome 17
• Autosomal recessive disorder
• Diagnosis: Determining activity of acid alpha-glucosidase enzyme
• Muscle weakness and heart problems are the most common features even though defected enzyme is present in all tissues
GSD Type III / Cori Disease
• Caused by mutation in gene responsible for making the glycogen debranching enzyme
• It is inherited and leads to abnormal glycogen in the body• Divided into types IIIa, IIIb, IIIc, IIId • Affects 1 in 100,000 individuals, whereas it affects 1 in 5,400
individuals of North African Jewish
GSD Type IV / Anderson Disease
• Caused by mutation in gene responsible for making the glycogen branching enzyme
• It is inherited and leads to abnormal glycogen in the body • Divided into 5 subtypes, which vary in severity, signs and
symptoms• Affects 1 in 600,000 to 800,000 individuals world wide
GSD Type V / McArdle disease
• Caused by mutation in gene which is responsible for myophosphorylase
• It is inherited and leads to inability to break down glycogen in muscle cells
• Symptoms include exercise intolerance marked by rapid fatigue and cramps in exercising muscles
• Generally rare but affects 1 in 100,000 individuals
GSD Type VIHers disease, liver phosphorylase deficiency
• Liver glycogen phosphorylase
• Early signs and symptoms frequently includes hepatomegaly and hypoglycemia; growth retardation, ketosis, and hyperlipidemia.
GSD Type VIITarui disease, muscle phosphofructokinase deficiency
• Phosphofructokinase (muscle)
• PFKM, chromosome 12
• Exercise intolerance (due to muscle pain, cramping, fatigue, and tenderness), myopathy, and hemolysis; myoglobinuria may develop (dark-red or red-brown urine)
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