Metabolism of pentoses,
glycogen, fructose and galactose
Jana Novotna
1. The Pentose Phosphate
Pathway
The pentose phosphate pathway (PPP):
(hexose monophosphate or 6-phosphogluconate patway)
• Process that generates NADPH and pentoses (5-carbon sugars).
• Enzymes are located in the cytosol.
• Rapidly dividing cells (bone marrow, skin, intestinal mucosa, tumors)
 ribose 5-phosphate  RNA, DNA.
• Other tissues  NADPH  electron donor for reductive biosynthetic
reactions
– fatty acids synthesis (liver, adipose tissue),
– cholesterol and steroid hormones synthesis (liver, adrenal glands,
gonads)
– elimination of oxygen radicals effects (erythrocytes).
An overview:
Two stages:
1) Oxidative (irreversible)
•
products:
→ ribose 5-phosphate (nucleotide synthesis)
→ NADPH (fatty acid synthesis, detoxification, reduction of
glutathion)
2) Nonoxidative (reversible)
•
conversion of ribose 5-phosphate to intermediates of
glycolysis
•
production of ribose 5-phosphate from intermediates of
glycolysis
1. The oxidative phase of PPP:
Regulation:
Glucose 6-phosphate dehydrogenase
• inhibition - by NADPH
• induction - by insulin/gluckagon ↑
Some concepts
• Isomers - molecules with the same molecular formula but
different chemical structures (glucose and fructose)
• Epimeres - differ at only one chiral center, not the anomeric
carbon.
• Enantiomers - chiral molecules that are mirror images of one
another.
Epimers
Enantiomers
2. The nonoxidative phase of PPP:
Pathways that require NADPH:
Detoxification
• reduction of oxidized glutathione
• cytochrome P450 monooxygenases
Reductive synthesis
• fatty acid synthesis
• fatty acid chain elongation
• cholesterol synthesis
• steroid hormon synthesis
• neurotransmitter synthesis
• deoxynucleotide synthesis
The role of PPP in maintenance of the erythrocyte
membrane integrity:
Clinical correlations:
Treatment by certain drugs (i.e. sulfonamides)
 people with glucose 6-phosphate dehydrogenase deficiency (7% of
the world population)
 increased production of free radicals
reduced protection of erythrocytes against FR
 hemolysis, hemoglobinuria, hemolytic anemia
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
• The glycogen – a storage form of glucose
• Required as a ready source of energy
• The liver – tremendous capacity for storing glycogen –
10% of the wet weight
• Muscle – max.1 – 2% of the wet weight
• Muscle and liver glycogen stores serve completely
different roles:
– muscle glycogen – fuel reserve for ATP synthesis
– liver glycogen – glucose reserve for the maintenance of blood
glucose concentration
Glucosyl units of α-D-glucose linked by 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 glycogen metabolism in the muscles and the liver:
Decrease in glucose in the blood
→ glycogen degradation
High ATP demand
→ release of glucose to the blood
→ glycogen degradation
Glucose 6-phosphatase (only in
liver)
→ anaerobic glycolysis
Glycogen metabolism - an overview:
Synthesis and degradation of glycogen:
→ different enzymes (regulation!)
UDP-glucose – the substrate for glycogen synthesis and UDP is released as a
reaction product
glucose-1-phosphate + UTP  UDP-glucose + PPi
PPi + H2O  2 Pi
Overall: glucose-1-phosphate + UTP  UDP-glucose + 2 Pi
Cleavage of PPi is the only energy cost for glycogen synthesis (one ~P
bond per glucose residue).
Glycogenin - (enzyme) initiates glycogen synthesis.
Glycogen synthesis:
 A glycogen primer - 4 attached glucose
molecules to glycogenin
- not degraded
- synthesis autocatalytic glycosylation,
autophosphorylation of glycogenin)
Transfer of 6-8 units
 Glycogen synthase (regulation)
 An energy-requiring pathway (UTP)
Glycogen degradation:
 Chain cleavage (phosphorolysis) –
glycogen phosphorylase
- to 4 units from a branch point
-The debrancher enzyme - amylo-16
glukosydase (transfer of 3 units, hydrolysis of 1
glucose)
-two catalytic activities – transferase + a-16glucosydase
 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
Regulation of glycogen synthase
by covalent modification
Regulation of glycogen phosphorylase
by covalent modification
Regulation of glycogen synthesis and degradation in the liver
Activation of muscle glycogen phosphorylase
during exercise
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
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)