Overview Structure glycogen polymer of glucose straight chain with α-1,4-bond branches with α-1,6-bond glycogen granule core glycogenin Function energy reserves that can provide glucose during a fast or ↑ energy demand supplies exhausted in < 24 hrs stored mainly in the liver and muscle muscle does not have glucose-6-phosphatase so it cannot release free glucose stores for its own consumption liver does have glucose-6-phosphatase so it can release free glucose can use supplies to maintain blood glucose levels Glycogenesis Glycogen synthesis Pathway glucose-6-phosphate converted to glucose-1-phosphate UDP group added to form UDP-glucose UDP-glucose added to polymer in an α-1,4 linkage catalyzed by glycogen synthase rate limiting step of glycogen synthesis polymer rearranged to create α-1,6 linked branches catalyzed by branching enzyme deficiency = Anderson disease Regulation glycogen synthase in liver activated by insulin inhibited by glucagon, epinephrine in muscle activated by insulin inhibited by epinephrine Glycogenolysis Glycogen catabolism Pathway glucose-glucose bond broken by addition of a phosphate catalyzed by glycogen phosphorylase rate limiting step of glycogenolysis hepatic deficiency = Hers disease (type VI) muscle deficiency = McArdle disease (type V) glucose-1-phosphate freed converted to glucose-6-phosphate debranching enzymes removes α-1,6 linked branches deficiency = Cori's disease (type III) liver converts glucose-6-phosphate to glucose catalyzed by glucose-6-phosphatase deficiency = von Gierke disease (type I) muscle puts glucose-6-phosphate into glycolysis Regulation glycogen phosphorylase in liver activated by epinephrine, glucagon via cAMP/protein kinase A inhibited by insulin remember: exact opposite of glycogen synthase hepatic glycogen regulatory processes both turn on forward direction and turn off reverse in skeletal muscle activated by epinephrine, AMP, Ca2+ inhibited by insulin, ATP remember: since muscular glycogen can only supply itself, it is regulated by its own energy supply (AMP/ATP ratio); while liver must supply energy to many other tissues, it functions independently of AMP/ATP ratio in hepatocytes Glycogen Storage Diseases (Glycogenolyses) Overview all disorders have abnormal glycogen metabolism leads to an accumulation of glycogen within cells organ dysfunction remember: disorders numbered in order of pathway from end (glucose release) to beginning (breakdown of glycogen polymer) Glucose release Type I: von Gierke lacks glucose-6-phosphatase presentation liver cannot release stored glucose hepatomegaly severe hypoglycemia body must rely on fat/protein catabolism for energy hyperlipidemia hyperuricemia lactic acidosis normal glycogen structure tests stimulation test with glucagon, fructose, galactose does not ↑ serum glucose Lysosomal pathway Type II: Pompe "trashes the Pump (heart)" lacks lysosomal α1,4-glucosidase degrades glycogen-resembling material in endosomes presentation buildup of glycogen in cardiac muscle electron dense granules inside lysosomes cardiomegaly hypertrophic cardiomyopathy Branching/debranching Type III: Cori lacks debranching enzyme remember: Cori = can't Catabolize branches 6-pack core - alpha 1,6 glucosidase defective presentation liver cannot break down glycogen past a branch point hepatomegaly hypoglycemia abnormal glycogen structure short outer glycogen chains Type IV: Anderson lacks branching enzyme remember: Anderson = can't Add branches presentation liver cannot form branched glycogen granules hypotonia cirrhosis Phosphorylase Type V: McArdles lacks muscle phosphorylase remember: McArdles = Muscle can't breakdown glycogen to glucose-1-phosphate accumulation of glycogen in muscle tissue presentation muscle weakness/cramps upon exertion myoglobinuria normal glycogen structure Type VI: Hers lacks hepatic phosphorylase remember: Hers = Hepatic presentation hepatomegaly fasting hypoglycemia can be mild due to gluconeogenic compensation