What are the types of chains present in the glycogen structure?
Inner B-chains (2 branchpoints)
Outer A-chains (unbranched)
What is the general structure of glycogen?
12 tiers of chains w/ ˜55000 glucose residues
Molecular mass of ˜107 kDa
Diameter of ˜44nm
What other types of molecules are present in glycogen besides glucose residues?
What enzyme is responsible for the addition of other molecules to the glycogen structure?
What are the effects of excessive phosphorylation of glycogen?
Lafora disease (epilepsy)
Multiple cycles of expansion and contraction cause chemical/metabolic insults that can accumulate, and results in aberrant structures that sometimes escape normal metabolism and degenerate into an insoluble deposit.
What are the locations of glycogen storage?
Skeletal muscle and liver (major deposit)
Other organs capable of glycogen synthesis are the kidney, heart, adipose, and brain.
What are the precursors and donors used in glycogen synthesis?
Precursor: Glucose (carbohydrate)
Precursor: Lactate or alanine (gluconeogenic)
Donor: Activated NDP-sugar UDP-glucose
What are the types of glucose transporters used in the direct pathway?
GLUT2 (prominent in liver and β-cells of pancreas, admits glucose based on positive glucose gradient between blood and tissue)
GLUT4 (up-regulated by insulin, important in insulin sensitive tissues like skeletal muscle and adipose)
How are the UDP-glucose, glycogenin primer and glycogen A&B chains synthesized?
UTP is converted to UDP by UDP-glucose pyrophosphorylase.
Glycogenin self-glucosylates to form oligosaccharide primer.
Glycogenin interacts with glycogen synthase which forms the majority of the α-1,4 glycosidic linkages.
α-1,6 glycosidic branchpoints are formed by branching enzyme.
What is the difference between the indirect and direct pathways for glycogen synthesis?
Indirect pathway=glyconeogenesis that occurs with gluconeogenic precursors (lactate, alanine, etc)
Direct pathway=requires transport of glucose into cells with GLUTs
What are the products of glycogen degradation?
Glucose-1-phosphate (from α-1,4 linkages)
Free glucose (from α-1,6 linkages)
What are the conditions that stimulate glycogen breakdown?
Nutritional deprivation (hepatic glycogenolysis)
Exercise (muscle glycogenolysis under conditions of increased cAMP and Ca2+)
How is the breakdown of glycogen mediated in the first pathway?
Actions of glycogen phophorylase.
Actions of debranching enzyme AGL.
How is the breakdown of glycogen mediated in the second pathway?
Glycogen is transferred to the lysosome and hydrolyzed to glucose by lysosomal α-glucosidase.
What is the biochemical function of glycogenin?
1. Transfers glucose from UDP-glucose to a tyrosine residue within the protein itself.
2. From there it forms α-1,4 glycosidic linkages until the oligosaccharide chain is 10-20 residues long.
What are the genes that encode glycogenin and how are they expressed?
GYG1: widely expressed
GYG2: expressed in liver, heart, pancreas
What type of gene mutation can cause glycogenin to be defective? What effect does this have on the patient?
Nonsense mutation in one allele and missense mutation (T83M) in the other which leads to inactive glycogenin-1.
Patient has muscle weakness and cardiac abnormalities following exercise.
What is the biochemical function of glycogen synthase?
It is responsible for the bulk synthesis of glycogen by formation of the α-1,4 linkages with UDP-glucose as the glucosyl donor.
What are the genes that encode glycogen synthase in mammals and how are they expressed?
GYS1: expressed in skeletal muscle and most other cells capable of glycogen synthesis
GYS2: expression restricted to liver
How is glycogen synthase regulated?
Allosteric activation by glucose-6-phosphate
What are the types of glycogen synthase mutations, and what are they physiological effects on patients?
Mutation of GYS2 (GSD 0): causes hepatic glycogen deficiency. Patients have mild symptoms, postprandial hyperglycemia, and fasting hypoglycemia. Hepatic glycogen synthase activity is reduced.
Mutation of GYS1: glycogen synthase and glycogen are absent from muscle. Causes cardiac problems, and poor exercise performance. Occurs as a result of a homozygous mutation of R462X in GYS1.
What are the enzymes involved in the rate-determining steps of glycogen synthesis in muscle?
Name the general location of glycogen storage inside cells.
What is glycogen autophagy?
Autophagy is comprised of processes described as a mechanism for random recycling of cellular materials under conditions of nutritional deprivation.
The term glycogen autophagy has been applied particularly to the liver of newborns.
What is the location of glycogen in liver and muscle cells?
Close to membranes, endoplasmic reticulum (liver), sarcoplasmic reticulum (muscle).
What are the causes and physiological effects of Lafora Disease?
'Lafora bodies' are deposits containing poorly branched, insoluble glycogen-like carbohydrate (polyglucosan) in individuals with an autosomal recessive neurodegenerative disorder called Lafora Disease.
Causes progressive myoclonus epilepsy, dementia and death (within 10 years of symptoms starting).