Lecture 43

Question 1

energy production in muscle

Answer 1

glucose-6-phosphate converted to glycogen via glycogenesis and back via glycogenolysis

pg 1146

Question 2

glycogen storage: locations

Answer 2

• liver and muscle are designed to store large amounts of glycogen
• glycogen in liver ensures constant supply of glucose in bloodstream
• glycogen in muscle allows it to be able to work when no insulin is in the system (when first wake up) -> used for energy WITHIN muscle cells
• muscle stores more glycogen than the liver

pg 1147

Question 3

glycogen structure

Answer 3

branched glucose with α(1,4) and α(1,6) glycosidic bonds

pg 1148

Question 4

why glycogen branches are important

Answer 4

1. increase the solubility of glycogen molecules
2. increase the number of nonreducing ends which allows for faster synthesis and degradation to be achieved

glycogen stored in cytosol; enzymes attach on non-reducing ends to break down or synthesize; fast degradation important in maintaining blood glucose levels

pg 1149

Question 5

glycogen metabolism overview

Answer 5

each process (glycogenolysis or glycogenesis) has their own set of enzymes for precise regulation

• glycogenolysis (glycogen degradation) occurs when glucose is needed
• glycogenesis (glycogen synthesis)

pg 1150

Question 6

glycogenesis: synthesis of UDP-glucose

Answer 6

• glucose-6-phosphate converted to glucose-1-phosphate in a reversible reaction using enzyme phosphoglucomutase (only enzyme in both synthesis and degradation -> transfers phosphate group)
• glucose-1-phosphate and UTP use UDP-glucose phosphorylase to form uridine diphosphate glucose (UDP-glucose) and releases 2 inorganic phosphates
• UDP-glucose is glucose attached to the carrier location of UDP

pg 1151

Question 7

glycogenesis: glycogenin

Answer 7

• homodimer protein
• serves as a primer for glycogen synthesis
• Tyr is an attachment point for UDP-glucose
• glycogenin has catalytic glucosyltransferase activity (α(1,4) glycosidic bonds)

pg 1152

Question 8

glycogenesis: glycogen synthase

Answer 8

• rate-limiting regulatory step
• elongates the existing glycogen primers by transferring UDP-glucose to the non-reducing end of the core
• forms α(1,4) glycosidic bonds ONLY between C-1 of UDP-glucose and C-4 from the primer

pg 1153-1154

Question 9

glycogenesis: branching enzyme

Answer 9

aka amylo α(1,4):α(1,6)-transglucosidase

• removes a chain of 6-8 glucosyl residues from the end of the glycogen chain (breaks an α(1,4) bond)
• attaches it to a non-terminal glucosyl residue by an α(1,6) bond
• functions as a 4:6 transferase

pg 1155

Question 10

glycogenolysis: glycogen phosphorylase

Answer 10

• rate-limiting regulatory step
• tissue-specific isoforms: liver, muscle, brain
• sequentially cleaves α(1,4) glycosidic bonds from the nonreducing ends
• uses inorganic Pi to cleave the bond and simultaneously attaches it to the glucose
• STOPS when the chain has been shortened to 4 remaining glucosyl units from a branch point
• requires pyridoxal phosphate (PLP, from vitamin B6) as a coenzyme

pg 1157

Question 11

glycogenolysis: debranching enzyme

Answer 11

• single protein with 2 activities
• 4:4 transferase activity -> removes 3 of the 4 glucosyl residues at the end of the chain breaking an α(1,4) bond and transfers them to the end of another chain creating an α(1,4) linkage
• 1:6 glucosidase activity -> removes the remaining single glucose residue attached via α(1,6) linkage at the branch point to yield a free glucose
• glycogen phosphorylase then takes over and degradation continues

pg 1158-1159

Question 12

glycogenolysis: fate of glucose-1-phosphate

Answer 12

• phosphoglucomutase is an enzyme that converts G-1-P back to G-6-P
• forms intermediate glucose-1,6-bisphosphate
• activated by 1,6-bisphosphate
• modified by Ser-phosphorylation at the catalytic site

pg 1160

Question 13

regulation of glycogen metabolism

Answer 13

• reciprocal regulation -> regulated in opposite manners
• liver: synthesis activated in well-fed state, degradation activated during fasting
• muscle: synthesis activated at rest, degradation activated during exercise
• allosteric regulation in muscle: phosphorylase activated by AMP (low energy), Ca2+ (muscle contraction) and inhibited by glucose-6-P and ATP; synthase activated by glucose-6-P
• hormone regulation in muscle: phosphorylase activated by epinephrine and inhibited by insulin; synthase opposite (insulin signal of plenty glucose, epinephrine secreted in stress situations)

pg 1161-1162, 1164

Question 14

allosteric regulation in muscle

Answer 14

role of calcium in muscle: during muscle contraction, calcium is released from the SR; Ca2+ binds to the calmodulin subunit of phosphorylase kinase b, activating it without phosphorylation; phosphorylase kinase can then activate glycogen phosphorylase causing glycogen degradation

pg 1163

Question 15

degradation of glycogen in the lysosomes

Answer 15

enzyme: lysosomal α(1,4)-glucosidase

• product of a housekeeping gene
• regulated at the level of protein expression
• optimal pH 4.5
• only 1-3% of the glycogen degraded by this pathway
• the purpose of this pathway is not well understood
• deficiency leads to GSD type II

pg 1166

Question 16

Type II: Pompe disease

Answer 16

lysosomal α(1,4) glucosidase deficiency

• only GSD that is also a lysosomal storage disease
• generalized (but primarily heart, liver, muscle)
• excessive glycogen in lysosomes
• normal glycogen structure
• normal blood sugar levels
• hypotonia and muscle weakness
• massive cardiomegaly
• infantile form: frequently fatal due to heart failure
• enzyme replacement therapy available

pg 1166

Question 17

glycogen storage diseases (GSD)

Answer 17

see slide!!!

pg 1167

Question 18

Type III: Cori Disease

Answer 18

4:4 transferase and/or amylo-α(1,6)-glucosidase (debranching enzyme) deficiency

• fasting hypoglycemia
• abnormal glycogen structure with four or one glucosyl residues at branch points (inability to be removed)
• different degrees of organ dysfunction
• hepatomegaly, myopathy

pg 1168

Question 19

Type IV: Andersen Disease

Answer 19

branching enzyme (amylo α(1,4):α(1,6)-transglucosidase; 4:6 transferase)

• abnormal glycogen molecules called polyglucosan bodies accumulate in cells, leading to damage and cell death
• accumulate in cells throughout the body, but liver cells and muscle cells are most severely affected
• five types -> 3 muscular and 2 hepatic
• symptoms: hypotonia, muscle wasting, dilated cardiomyopathy, myopathy, early liver disease

pg 1169

Question 20

Type V: McArdle Syndrome

Answer 20

skeletal muscle glycogen phosphorylase or myophosphorylase deficiency

• SKM affected; liver enzyme normal
• temporary muscle weakness and cramping of SKM after exercise
• NO rise in blood lactate during strenuous activity
• myoglobinemia and myoglobinuria may be seen
• relatively benign, chronic condition
• high level of glycogen with normal structure in muscle

pg 1170

Question 21

Type VI: Hers Disease

Answer 21

deficiency of the liver isozyme (liver glycogen phosphorylase deficiency)

• mild fasting hypoglycemia: no glucose from glycogen, but gluconeogenesis is still functional
• hepatomegaly and cirrhosis: excessive buildup of glycogen in liver

pg 1170

Question 22

Type VII: Tarui Disease

Answer 22

phosphofructokinase - M type

• PFK-1 tetrameric enzyme that consists of three types of subunits arranged in different combinations in different tissues (PFKL - liver, PFKM - muscle, PFKP - platelet)
• 4 types of Tarui disease: classical form, severe infantile form, late-onset form, hemolytic form
• classical: most common, muscle pain and cramps post-exercise; in strenuous exercise -> nausea and vomiting, myoglobinuria
• severe infantile: hypotonia, muscle weakness, cardiomyopathy, difficulty breathing
• late-onset: myopathy is only feature
• hemolytic: hemolytic anemia -> muscles not affected

pg 1171