Lecture 43 Flashcards
Muscle Energy Metabolism: Glycogen Metabolism
energy production in muscle
glucose-6-phosphate converted to glycogen via glycogenesis and back via glycogenolysis
pg 1146
glycogen storage: locations
- 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
glycogen structure
branched glucose with α(1,4) and α(1,6) glycosidic bonds
pg 1148
why glycogen branches are important
- increase the solubility of glycogen molecules
- 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
glycogen metabolism overview
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
glycogenesis: synthesis of UDP-glucose
- 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
glycogenesis: glycogenin
- 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
glycogenesis: glycogen synthase
- 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
glycogenesis: branching enzyme
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
glycogenolysis: glycogen phosphorylase
- 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
glycogenolysis: debranching enzyme
- 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
glycogenolysis: fate of glucose-1-phosphate
- 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
regulation of glycogen metabolism
- 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
allosteric regulation in muscle
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
degradation of glycogen in the lysosomes
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
Type II: Pompe disease
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
glycogen storage diseases (GSD)
see slide!!!
pg 1167
Type III: Cori Disease
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
Type IV: Andersen Disease
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
Type V: McArdle Syndrome
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
Type VI: Hers Disease
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
Type VII: Tarui Disease
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
