Post on 17-Jan-2016
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
→ glycogen degradation
→ release of glucose to the blood
Glucose 6-phosphatase (only in liver)
High ATP demand
→ glycogen degradation
→ anaerobic glycolysis
Glycogen metabolism-overview:
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)
Type Enzyme affected Genetics Organ involved
Manifestations
I (Von Gierke´s disease)
Glucose 6-phosphatase
AR (1/200 000)
Liver Hypoglycemia, lactate acidosis, hyperlipidemia, hyperuricemia.
Enlarged liver and kidney.
II (Pompe disease)
Lysosomal α-1,4-glucosidase
AR Organs with lysosomes
Glycogen deposits in lysosomes.
Hypotonia, cardiomegaly, cardiomyopathy (Infantile f.).
Muscle weakness (Adult f.)
III (Cori´s disease)
The debrancher enzyme
AR Liver, muscle, heart
Hepatomegaly, hypoglycemia
V (McArdles disease)
Muscle glycogen phosphorylase
AR Muscle Exercise-induced muscular pain, cramps, muscle weakness
Glycogen storage diseases:
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
State Regulators Response
Liver
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 ↓
Muscle
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 ↑
Regulation of liver and muscle glycogen metabolism:
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
Principally in the liver (small intestine, kidney)
Aldolase B: low affinity for fructose 1-phosphate (→ accumulation of fructose 1-phosphate in the liver )
Fructose metabolism
Essential fructosuria
Hereditary fructose intolerance
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)