glycogen Flashcards
What is the only organ that can make glucose?
liver
what is the preferred energy source for the brain and required for RBCs?
glucose
constant levels of blood glucose
absolute requirement
what is essential for exercising muscle?
glucose
Where is glucose obtained from?
- diet
- GNG (fasting)
- Glycogen stores (quick energy)
Acetyl CoA
CANNOT make glucose
dietary intake of glucose
- sporadic
- dependent on the diet content
- not always reliable source of blood glucose
GNG and glucose
- can provide sustained synthesis of glucose
- BUT it is somewhat slow in responding to a falling blood glucose levels
glycogen and glucose
-mechanisms for storing a supply of glucose in a rapidly mobilizable form
glycogen tissue distribution
-virtually any cell in the body may contain glycogen (high levels can be damaging)
Main stores of glycogen
skeletal muscle
liver
glycogen in skeletal muscle
- for its own use as a fuel source
- Can never exit skeletal muscle
- 400g
- 1-2% fresh weight of resting muscle
glycogen in liver
- maintain blood glucose during early fasting
- goal is to be released to maintain blood glucose levels
- 100g
- 10% of fresh weight of an adult well-fed liver
hepatocytes
will contain more glycogen than skeletal muscle
glycogen storage diseases
amount of glycogen stored in liver and skeletal muscle can be significantly higher or lower
absence of glucose
- glycogen is degraded to glucose and it rapidly released from liver and kidney glycogen
- muscle glycogen is extensively degraded in exercising muscle to provide that tissue with an important energy source
as glycogen stores are depleted
the synthesis of glucose (gluconeogenesis) takes over, therefore glycogen serves as a glucose source in the gap between the fall of blood glucose hours after a meal and the onset of gluconeogenesis which needs time to kick in and occurs a few hours later
glycogen structure
- branched chain polysaccharide made from a-D-glucose (linear)
- 10-40x10^3 glucose molecules in 1 glycogen granule
- primary glycosidic bond is a(1,4) linkage
- branch containing a(1,6) linkage every 8-10 glucose residues
discrete cytoplasmic granules (B-particles)
large molecules of glycogen
-associated with the enzymes necessary for the synthesis and degradation
glycogenesis
synthesis of glycogen
step 1 of glycogensis
synthesis of uridine diphosphate glucose
step1: synthesis of uridine diphosphate glucose
- a-D-glucose goes to glucose 6-P with enzyme hexo/glucokinase
- glucose 6-P goes to glucose 1-P with enzyme phosphoglucomutase
- UTP cleaves a phosphate and becomes UDP glucose
- highly endergonic
What does hexo/glucokinase do to a-D glucose
turns it to glucose 6-P and traps it in the cell
What drives the synthesis of UDP?
that fact that it’s highly exergonic
step 2 of glycogenesis
synthesis of a primer to initiate glycogen synthesis
glycogen synthase
- CAN NOT add UDP glucose to a single glucose molecules
- It can ONLY ELONGATE existing glycogen molecules (primers)
if no glycogen primers are available
- protein glycogenin serves as a primer
- specific Tyr residue serves as attachment point for glycogen synthase
- glycogenin itself catalyzes this attachment reaction and the attachment of next few UDP-glucose molecules via a(1,4) glycosidic bond
step 3 of glycogenesis
elongation of glycogen chains
step 3: elongation of glycogen chains
-enzyme: glycogen synthase
glycogen synthase
- elongates the existing glycogen primers
- transfer UDP-glucose to the non-reducing end of the primer
- forms a(1,4) glycosidic bonds ONLY between C-1 of UDP glucose and C-4 from the primer
- rate limiting enzyme
What bonds does glycogen synthase form?
a(1,4) glycosidic bonds ONLY between C-1 of UDP glucose and C4 from the primer
What kind of bonds does glycogenic form between the UDP glucose molecules?
a(1,4)glycosidic bonds
What is the primary glycosidic bond of glycogen?
a(1,4) linkage
What type of bond is there every 8-10 glucose residues on glycogen?
branch containing a(1,6) linkage
step 4 of glycogenisis
formation of branches
Step 4: formation of branches
- enzyme: branching enzyme (amylo…)
- removes a chain of 6-8 glucose residues from the end of the glycogen chain (breaks an a(1,4) bond)
- attaches it to an non-terminal glucose residue by an a(1,6) bond
- functions as a 4:6 transferase
What does the branching enzyme function as?
4:6 transferase
degradation of glycogen (glycogenolysis)
- NOT a simple reversal of the glycogenesis
- separate set of enzymes
- 4-step pathway
4 step pathway of glycogenolysis
- shortening of chains
- removal of branches
- conversion of glucose 1-P to glucose 6-P
- conversion of glucose-6-P to glucose (LIVER ONLY)
step 1 of glycogenolysis
shortening of the chains
shortening of the chains
- step 1 of glycogenolysis
- enzyme glycogen phosphorylase
glycogen phosphorylase
- step 1 of glycogenolysis
- rate limiting regulatory step
- tissue specific isoforms: liver, brain, muscle
- sequentially cleaves a(1,4) glycosidic bonds from the ends of the glycogen chains
- uses inorganic Pi to cleave the bond and simultaneously attaches it to the glucose
- yields glucose 1-P
- stops when the chain has been shortened to 4 remaining glucosyl units from a branch point
- Requires PLP (derived from it B6) as a coenzyme
limit dextrins
- shortening of chains for glycogenolysis stops here.
- 4 remaining glucosyl units
- cannot fit very well with the active center of enzyme at this point
Step 2 of glycogenolysis
removal of branches
enyme is debranching enzyme
debranching enzyme
- removal of branches
- single protein with 2 activities (2 different active sites)
- 4:4 transferase activity
- 1:6 glucosidase activity
(HAPPEN SIMULTANEOUSLY)
4:4 transferase activity of debranching enzyme
- removes 3 of the 4 glucosyl residues at the end of a chain breaking an a (1,4) bond
- transfers them to the end of another chain creating an a(1,4) linkage
1:6 glucosidase activity of debranching enzyme
- removes the remaining single glucose residue attached via a(1,6) linkage at the branch point
- yields free glucose (no Pi)
Step 3 og glycogenolysis
conversion of glucose 1-P to glucose 6-P
enzyme is phosphoglucomutase
phosphoglucomutase
- enzyme for conversion of glucose 1-P to glucose 6-P
- forms intermediate glucose-1,6-bisP
- activated by glucose 1-6-bis-P
- modified by Ser-phosphorylation at the catalytic site
step 4 of glycogenolysis
- dephosphorylation of glucose 6-P to glucose
- enzyme is glucose 6-phosphatase
glucose 6-Phosphatase
- dephosphorylation of glucose 6-P to glucose
- expressed in liver and kidney cortex
- expressed lesser in the pancreatic B-cells and intestinal mucosa
- ER transmembrane protein with active sites facing ER lumen
- a complex of multiple component proteins
glucose 6-Phosphatase complex
- complex of multiple component proteins
- 3 transporters: G6PT1, 2, 3
- catalytic subunit- G6Pase-a-B
degradation of glycogen in the lysosomes
- lysosomal a(1,4)-glucosidase
- product of housekeeping gene
- regulated at the level of protein expression
- optimal pH=4.5
- only about 1-3% of the glycogen
- purpose of this pathway not well understood
regulation of glycogenesis in tissues
liver- in well fed state
muscle- begins at rest
regulation of glycogenolysis in tissues
liver-during fasting
muscle- during exercise
What are regulatory enzymes of glycogenesis and glcogenolysis?
glycogen synthase and glycogen phosphorylase
how is enzyme regulation in glycogenesis and glycogenolysis accomplished at 2 levels?
- hormonal regulation to meet the needs of the body as a whole
- Allosteric regulation to meet the needs of the particular tissue
What is glycogen phosphorylase activated by in the liver?
hormonal
- epinephrine
- glucagon
Allosterically
-none
what is glycogen phosphorylase activated by in the muscle?
homronal
-epinephrine
allosterically
- AMP
- Ca2+
What is glycogen phosphorylase inhibited by in the liver?
hormonal
-insulin
allosterically
- glucose 6-P
- glucose
- ATP
What is glycogen phosphorylase inhibited by in the muscle?
hormonal
-Insulin
allosterically
- Glucose 6-P
- ATP
What is glycogen synthase activated by in the liver?
hormona
-insulin
allosterically
-glucose 6-P
What is glycogen synthase activated by in the muscle?
hormonal
-insulin
allosterically
-glucose 6-P
What is glycogen synthase inhibited by in the liver?
hormonal
- glucagon
- epinephrine
allosterically
-none
What is glycogen synthase inhibited by in the muscle?
hormonal
-epinephrine
allosterically
-none
Why are branches important?
- increases solubility
- increases surface area
- more enzymes
- faster degradation
- more nonreducing ends for faster synthesis and degradation
Von Gierke
deficient enzyme
-glucose 6-phosphatase (liver, kidney)
clinical features
- severe fasting hypoglycemia
- lactic acidosis
- hepatomegaly
- hyperlipidemia
- hyperurecemia
- short stature
glycogen structure
-normal
Pompe
deficient enzyme
-lysosomal a(1-4)-glucosidase
clinical features
- cardiomegaly
- muscle weakness
- death by 2 years
Glycogen structure
-glycogen-like material in inclusions
Cori
deficient enzyme
-debranching enzyme
clinical features
- mild hypoglycemia
- liver enlargement
glycogen structure
-short outer branches, single glucose residue at outer branch
Anderson
deficient enzyme
-branching enzyme
clinical features
- infantile hypotonia
- cirrhosis
- death by 2 years
- rare
glycogen structure
-very few branches, especially towards periphery
McArdle
deficient enzyme
-muscle glycogen phophorylase
clinical features
- muscle cramps and weakness on exercise
- myoglobinuria
glycogen structure
-normal
Hers
deficient enzyme
-hepatic glycogen phophorylase
clinical features
- mild fasting hypoglycemia
- hepatomegaly
- cirrhosis
glycogen structure
-normal
