Transcript Glycogen synthesis

Metabolism of pentoses,
glycogen, fructose and
galactose
Alice Skoumalová
1. The Pentose Phosphate
Pathway
An overview:
The pentose phosphate pathway (PPP):
 occurs in the cytosol
 in all cells
 Two stages:
1) Oxidative (irreversible)
•
Products:
→ Ribulose 5-phosphate (nucleotide synthesis)
→ NADPH (fatty acid synthesis, detoxification, reduction of
glutathion)
2) Nonoxidative (reversible)
•
Conversion of Ribulose 5-phosphate to intermediates of
glycolysis
•
Production of Ribulose 5-phosphate from intermediates of
glycolysis
1. The oxidative phase of PPP:
Regulation:
Glucose 6-phosphate dehydrogenase
• inhibition - by NADPH
• induction - by insulin/gluckagon ↑
2. The nonoxidative phase of PPP:
The role of PPP in maintenance of the erythrocyte membrane integrity:
Clinical correlations:
Treatment by certain drugs (i.e. sulfonamides)
 Increased production of free radicals
 People with glucose 6-phosphate dehydrogenase deficiency (7% of
the world population)
 reduced protection of erythrocytes against FR
 hemolysis, hemoglobinuria, hemolytic anemia
Pathways that require NADPH:
Detoxification
• Reduction of oxidized glutathione
• Cytochrome P450 monooxygenases
Reductive synthesis
• Fatty acid synthesis
• Fatty acid chain elongation
• Cholesterol synthesis
• Neurotransmitter synthesis
• Deoxynucleotide synthesis
•Superoxide synthesis
Summary:
The pentose phosphate pathway
 A shunt from glycolysis
 Production of NADPH (reductive syntheses, detoxifications),
ribose 5-phospate
 Conversion to intermediates of glycolysis
 Isomerases, epimerases, transketolases, transaldolases
 Glucose 6-phosphate dehydrogenase deficiency
2. Metabolism of glycogen
Glycogen
 α-D-Glucose, α-1,4 and α-1,6 link (branching every 8-10 units)
 source of energy in animals (liver, muscles)
 highly branched structure (rapid degradation and synthesis, better solubility)
Nonreducing end
glycogenin
The role of glycogen in muscles and liver:
Decrease in glucose in the blood
High ATP demand
→ glycogen degradation
→ glycogen degradation
→ release of glucose to the blood
→ anaerobic glycolysis
Glucose 6-phosphatase (only in
liver)
Glycogen metabolismoverview:
Synthesis and degradation of glycogen:
→ different enzymes (regulation!)
Glycogen synthesis:
 A glycogen primer
- not degraded
- synthesis (autophosphorylation of
glycogenin)
 Transfer of 6-8 units
 Glycogen synthase (regulation)
 An energy-requiring pathway (UTP)
Glycogen degradation:
 Chain cleavage (phosphorolysis)
- to 4 units from a branch point
- The debrancher enzyme
(transfer of 3 units, hydrolysis
of 1 glucose)
 Glycogen phosphorylase (regulation)
Glycogen storage diseases:
Type
Enzyme affected
Genetics
I (Von Gierke´s
Glucose 6phosphatase
AR
Liver
(1/200 000)
Hypoglycemia, lactate
acidosis, hyperlipidemia,
hyperuricemia.
Enlarged liver and kidney.
Lysosomal α-1,4glucosidase
AR
Organs
with
lysosomes
Glycogen deposits in
lysosomes.
Hypotonia, cardiomegaly,
cardiomyopathy (Infantile f.).
Muscle weakness (Adult f.)
The debrancher
enzyme
AR
Liver,
muscle,
heart
Hepatomegaly,
hypoglycemia
Muscle glycogen
phosphorylase
AR
Muscle
Exercise-induced muscular
pain, cramps, muscle
weakness
disease)
II (Pompe
disease)
III (Cori´s
disease)
V (McArdles
disease)
Organ
involved
Manifestations
Clinical correlations:
Maternal malnutrition in the last trimester of pregnancy
 (physiologically: glycogen formation and storage during the
last 10 weeks of pregnancy by the fetus → reserve for first
hours → prevention of hypoglycemia)
 reduced or no glycogen reserve in the fetus
 after birth → hypoglycemia, apathy, coma
Regulation of liver and muscle glycogen metabolism:
State
Regulators
Response
Fasting
Glucagon ↑, Insulin ↓
cAMP ↑
Glycogen degradation ↑
Glycogen synthesis ↓
Carbohydrate meal
Glu ↑, Glucagon ↓, Insulin ↑
cAMP ↓
Glycogen degradation ↓
Glycogen synthesis ↑
Exercise and stress
Adrenalin ↑
cAMP ↑, Ca2+-calmodulin ↑
Glycogen degradation ↑
Glycogen synthesis ↓
Fasting (rest)
Insulin ↓
Glycogen synthesis ↓
Glucose transport ↓
Carbohydrate meal (rest)
Insulin ↑
Glycogen synthesis ↑
Glucose transport ↑
Exercise
Epinephrine ↑
AMP ↑, Ca2+-calmodulin ↑,
cAMP ↑
Glycogen synthesis ↓
Glycogen degradation ↑
Glycolysis ↑
Liver
Muscle
Regulation of glycogenolysis in the liver by
glucagon:
cAMP → protein kinase A:
1. inactivates glycogen synthase
2. activates glycogen phosphorylase
Regulation of glycogenolysis in muscle:
Summary:
Glycogen metabolism
 Different role of glycogen stores in the liver and muscles
 Glycogen synthesis and degradation are separate pathways
(regulation)
 Glycogen storage diseases
3. Fructose and Galactose
metabolism
Fructose metabolism
Essential fructosuria
Hereditary fructose
intolerance
Principally in the liver (small intestine, kidney)
Aldolase B: low affinity for fructose 1-phosphate
(→ accumulation of fructose 1-phosphate in the liver )
The polyol pathway
Seminal vesicles (spermatozoa use fructose)
Accumulation of sorbitol in diabetic patients
 Lens (diabetic cataract)
 Muscles, nerves (periferal neuropathy)
Galactose metabolism:
Lens metabolism:
Diabetic cataract :
↑glucose concentration in the lens → ↑aldose reductase activity → sorbitol
accumulation → ↑osmolarity, structural changes of proteins
Clinical correlations:
A newborn: failure to thrive, vomiting and diarrhea after milk
 galactosemia (Galactose 1-phosphate uridylyltransferase
deficiency)
 genetic disease (AR, 1/60 000)
 hepatomegaly, jaundice, cataracts, mental retargation, death
Management: early diagnose, elimination of galactose from the diet
(artificial milk from soybean hydrolysate)
Summary:
Fructose and Galactose metabolism
 Conversion to intermediates of glycolysis
 Genetic abnormalities, accumulation of intermediates, tissue
damage
 Accumulation of sorbitol in diabetes
Pictures used in the presentation:
Marks´ Basic Medical Biochemistry A Clinical Approach, third edition, 2009 (M.
Lieberman, A.D. Marks)
Textbook of Biochemistry with Clinical Correlations, sixth edition, 2006 (T.M. Devlin)