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)