102 terms

Glycogen metabolism

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What is the optimum glucose concentration of the blood?
5 mmol/L
What are the 2 major sources of blood glucose?
diet

breakdown of hepatic glycogen stores
Glycogenesis
glycogen biosynthesis
Glycogenlysis
glycogen breakdown
Is glycogenesis endergonic or exergonic?
endergonic
What is the primer for glycogenesis?
glycogenin
What is the purpose of UDP-glucose?
the synthesis of sugar nucleotides is irreversible; it cannot be diverted to other pathways such as glycolysis

nucleotide moiety possesses groups that can undergo enzymatic noncovalent interactions and thus contributing to catalytic activity
What is the key regulatory enzyme of glycogenesis? Why?
glycogen synthase

UDP glucose is involved in glycolipid and glycoprotein synthesis
What type of bonds are formed by glycogen synthase?
alpha 1-4 glycosidic linkages in the main chain
What is the purpose of branch points (2)?
increase solubility of glycogen molecule

create numerous non-reducing ends for rapid synthesis and degradation
What is the rate-limiting step in glycogenolysis?
glycogen phosphorylase
What is the function of glycogen phosphorylase?
removes a single glucose-1-phosphate from the glycogen core
What enzyme rearranges glucose-1-phosphate to glucose-6-phosphate?
phosphoglucomutase
How does glucose leave the liver?
GLUT2
In what organelle is hepatic glucose-6-phosphatase located?
ER lumen
Name 2 allosteric activators of muscle glycogen phosphorylase
AMP

Ca2+
Name an allosteric inhibitor of muscle glycogen phosphorylase
glucose-6-phosphate
Describe the pathway of muscle activation and glycogenolysis
Beta-receptor (epinephrine)

cAMP

protein kinase A

phosphorylase kinase (phosphorylated)

glycogenolysis (glycogen phosphorylase a)

glycolysis

fructose-1,6-phosphate

TCA

oxidative phosphorylation
Does glucagon affect muscle cells?
glucagon has no effect on muscle
Where is glucagon produced?
pancreatic alpha-cells
Where is insulin produced?
pancreatic beta-cells
Where is epinephrine produced?
adrenal medulla
Name an activator of hepatic glycogen synthase
glucose-6-phosphate
Name 3 inhibitors of hepatic glycogen phosphorylase
glucose-6-phosphate

ATP

glucose
When is liver phosphorylase a active?
phosphorylated
When is liver phosphorylase inactive?
dephosphorylated
What type of receptor is the glucagon receptor?
G protein coupled receptor
Glycogen storage disease
inherited enzyme deficiencies that lead to the storage of glycogen in abnormal amounts and sometimes with an abnormal structure
von Gierke's disease
type 1: glucose-6-phosphatase deficiency
Pompe's disease
type 2: lysosomal alpha-1,4-glucosidase deficiency
Name 2 characteristics of hepatic glycogen storage diseases
hypoglycemia

hepatomegaly
Name 2 characteristics of myopathic glycogen storage diseases
muscle weakness and cramps
Which glycogenosis is found in muscle and liver?
type II: Pompe's disease
Pompe's disease
lysosomal alpha-1,4-glucosidase deificiency
What occurs in Pompe's disease?
glycogen builds up in lysosomes because lack of alpha-1,4-glucosidase deficiency
What structures are particularly affected in Pompe's disease?
brain and spinal cord
McArdle's disease
type V: muscle glycogen phosphorylase deficiency

limited ATP production

liver enzymes are normal
Does McArdle's disease affect liver enzymes?
no
What is myoglobinuria? Which glycogenosis is associated with myoglobinemia?
myoblogin in urine

McArdle's disease
What blood marker would suggest McArdle's disease?
increased CKMM
What is the prognosis for McArdle's disease?
avoid strenuous exercise
McArdle's Rx
sucrose drink prior to exercise

high-protein diet increases exercise tolerance

creatine supplement improves muscle
Tarui's disease
type VII: muscle phosphofructokinase-1 (PFK-1) deficiency and partial deficiency in erythrocytes
Symptoms of what glycogenosis are similar to Tarui's disease
Type V: McArdle's disease
How was Tarui's disease discovered?
blood lactate failed to rise following ischemic exercise test
Name the 4 liver glycogenoses
type I: von Gierke

type III Cori

type IV: Andersen

type VI: Hers
von Gierke disease
type 1a: glucose-6-phosphatase deficiency in liver, intestinal mucosa and kidney
Failure to degrade glucose-6-phosphate results in?
hepatomegaly
type Ib glycogen storage disease
deficiency in glucose-6-phosphate transporter
Why does hypoglycemia leads to excessive TAG degradation in adipose tissue?
insulin levels drop, leading to activation of hormone-sensitive lipase, free fatty acids for energy
List 4 changes in blood chemistry for type I glycogen storage diseases
hypoglycemia

lactic acidemia

hyperlipidemia

ketosis
von Gierke disease Rx (2)
provide carbohydrates (uncooked cornstarch fluid)

CHO infusion during sleep
Cori or Forbe's disease
type III: glycogen debranching enzyme of the liver, myocardium and skeletal muscle
List the presentation of Cori's disease (3)
hypoglycemia

hepatomegaly

progressive myopathy
Cori disease Rx (2)
stabilize hypoglycemic state

increased dietary protein intake to enhance gluconeogenesis
Andersen's disease
type IV: branching enzyme deficiency (amylo-1,4-1,6-transglucosidase)
List 2 symptoms of Andersen disease
hepatosplenomegaly

cirrhosis and liver failure
Anderson's disease Rx
liver transplant
Hers disease
type VI: liver glycogen phosphorylase deficiency
Name 4 symptoms of Hers disease
hepatomegaly

less severe hypoglycemia

lipidemia

acidosis
Why is hypoglycemia mild in Hers disease?
liver can still make glucose from pyruvate
Which disease is similar to Hers disease?
type I
What is the function of glycogen phosphorylase?
release glucose-1-phosphate by breaking alpha-1,4-bonds
GSD Type O
hepatic glycogen synthase deficiency
Name 2 symptoms of GSD0
no glycogenesis

hypoglycemia
Describe the structure of glycogen
alpha(1,4) glycosidic bonds

alpha(1,6) glycosidic branches every 8-12 residues
What transfers -OH group to glycogenin?
tyrosine residue
To which end are glucose unit added?
non-reducing ends
What is UDP-glucose?
group transfer reagent carrying an activated form of glucose
Glucokinase requires which co-factor?
Mg2+
What enzyme catalyzes the reaction from glucose-6-phosphate to glucose-1-phosphate?
phosphoglucomutase
What is the function of transferase?
removes branch moieties and adds them onto the glycogen core
What enzyme removes branches from the glycogen core?
debranching enzyme
In what situation does glycogenolysis occur in muscle tissue?
prolonged exercise
Describe the dual stimulation of muscle activation and glycogenolysis
Ca2+-calmodulin complex and AMP on phosphorylase kinase

AMP stimulates PFK-1 and and thus glycolysis

AMP stimulates phosphorylase kinase
Are muscle and liver tissues affected by insulin?
yes, both
Hypoglycemia will lead to secretion of what hormone(s)?
glucagon

adrenaline
Hyperglycemia will lead to secretion of what hormone(s)?
insulin
How does glucagon affect glycogenolysis?
rapid activation
How does insulin affect glycogenolysis?
inhibitory
How does adrenaline affect glycogenolysis?
rapid activation
In glycogenesis, which form of hepatic glycogen synthetase is active?
dephosphorylated
In glycogenolysis, which form of hepatic glycogen phosphorylase is active?
phosphorylated
Name an activator of muscle glycogen synthase
glucose-6-phosphate
Name 2 activators of muscle glycogen phosphorylase
Ca2+

AMP
Name 2 inhibitors of glycogen phosphorylase
glucose-6-phosphate

ATP
Explain what happens when glucagon binds to its receptor (up until phosphorylation events)
glucagon binds to its receptor, causing GDP to become GTP; this activates the g-protein

adenylyl cyclase creates cAMP from ATP

cAMP activates protein kinase A
Describe the effects of protein kinase A on Inhibitor - I
protein kinase A phosphorylates inhibitor-I, which becomes active

inhibitor - I inhibits phosphoprotein phosphatase, which is responsible for converting glycogen phosphorylase to its inactive form
Describe the effects of protein kinase A on phosphorylase kinase
protein kinase A phosphorylates phosphorylase kinase-b, which activates the enzyme

phosphorylase kinase-a phosphorylates glycogen phosphorylase-b, which becomes active

glycogen phosphorylase-a can then activate glycogenolysis
Describe the effects of protein kinase A on glycogen synthase
protein kinase A phosphorylates glycogen synthase-a, which becomes inactive
In muscle, how can phosphorylase kinase be activated without phosphorylation?
Ca2+ binds to the calmodulin subunit of phosphorylase kinase, activating it without phosphorylation
What is the main mechanism behind anti-glucagon effects?
dephosphorylation of glycogen synthase (activates the enzyme)
List 4 sources of energy for metabolizing myocytes
glucose from muscle glycogen

blood glucose (from liver glycogen)

creatine phosphate

mitochondrial aerobic catabolism of fatty acids
Name the 3 muscle glycogenoses
type II: Pompe's disease

type V: McArdle's disease

type VII: Tarui's disease
How does Pompe disease present (3)?
excessive glycogen concentrations in abnormal vacuoles

normal blood sugar levels

massive cardiomegaly
For McArdle's disease, would blood lactate rise during strenuous exercise?
no
McArdle Dx
function assay phosphorylase activity in cultured fibroblasts
How does von Gierke's disease present (5)?
fasting hypoglycemia

fatty liver

hepatomegaly

growth retardation and delayed puberty

hyperlacticacidemia
Why does lactic acidemia result from von Gierke's disease?
liver cannot utilize lactate efficiently for gluconeogenesis

in the absence of glucose-6-phosphatase, glucagon enhances lactate production in hepatocytes

glucose-6-phosphate is trapped inside cell and is degraded by glycolysis
Why does von Gierke's disease lead to hyperlipidemia?
lactate used for hepatic lipogenesis

low insulin:glucagon ratio favors TAG mobilization
von Gierke disease Dx
blood concentrations of glucose, cholesterol, TAG and lactate

ultrasound liver and kidneys

assay glucose-6-phosphatase activity

DNA testing is definitive

neutropenia
Name 2 symptoms of Pompe's disease
cardiomegaly

hepatomegaly