Metabolism of pentoses,

glycogen, fructose and

galactose

Karel Kotaska

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).

The pentose phosphate pathway (PPP)

Oxidation

Isomerization

and epimerization

C-C bond cleaving and formation

Regulation:

Glucose 6-phosphate dehydrogenase

• inhibition - by NADPH

• induction - by insulin/glucagon ↑

1. The oxidative phase of PPP:

Oxidative (irreversible) products:

→ ribose 5-phosphate (nucleotide

synthesis)

→ NADPH (fatty acid synthesis,

detoxification, reduction of

glutathion)

Some concepts

• Isomers - molecules with the same molecular formula but different chemical structures (glucose and fructose)

• Epimers - 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:

Nonoxidative (reversible)

→ conversion of ribose 5-phosphate to intermediates of glycolysis

→ production of ribose 5-phosphate from intermediates of glycolysis

Transketolase mechanism

E - transketolase

Transaldolase metabolism

Relationship between glycolysis

and pentose phosphate pathway

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

Summary of the pathways requiring NADPH+

The role of PPP

in maintenance of the erythrocyte

membrane integrity

-Antioxidant

-Xenobiotic metabolism

-Amino acid transport

PPP in liver

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

Fava beans

Favism

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 metabolism

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

Glycogen storage during the day

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

Glycogen

Glycogen

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).

Glycogen synthesis

Glycogenin - (enzyme) initiates glycogen synthesis.

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)

Chain cleavage (phosphorolysis) –

glycogen phosphorylase

- to 4 units from a branch point

-The debrancher enzyme - amylo-16

glukosydase (transfer of 3 units, hydrolysis of 1

glucose)

-two catalytic activities – transferase + a-16-

glucosydase

Glycogen phosphorylase (regulation)

Glycogen degradation:

The glycogen metabolism in the muscles and the 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

The glycogen metabolism in the muscles and the liver:

Regulation of glycogen

metabolism

Glycogen synthase

Covalent modification

Regulation of glycogen synthesis and degradation in the liver

Activation of muscle glycogen phosphorylase

during exercise

Regulation of phosphatase-1 in

muscle

Regulation of

glycogensynthase in muscle

Hormonal control of

glycogene metabolism

Regulation of

glycogenphosphorylase in muscle

Regulation of glycogen synthesis and degradation

Phosphorylation and

dephosphorylation in muscles

Control of glycolysis and

glycogenesis

cAMP dependent protein kinase

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:

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

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 (McArdle

disease)

Muscle glycogen

phosphorylase

AR Muscle Exercise-induced muscular

pain, cramps, muscle

weakness

Glycogen storage diseases:

G6P Deficiency

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 Galactose and

other hexoses metabolism

Fructose metabolism

Fructose metabolism

Essential

fructosuria

Hereditary fructose

intolerance

Fructose metabolism

Adequate diet Low glucose

Aldolase A: in all tissues

(small intestine, kidney)

Aldolase B: low affinity for

fructose 1-phosphate (→

accumulation of fructose

1-phosphate in the liver )

Fructose metabolism in muscle

The polyol pathway

Seminal vesicles (spermatozoa use fructose)

Accumulation of sorbitol in diabetic patients

Lens (diabetic cataract)

Muscles, nerves (periferal neuropathy)

Lens metabolism:

Diabetic cataract :

↑glucose concentration in the lens → ↑aldose reductase activity → sorbitol

accumulation → ↑osmolarity, structural changes of proteins

Galactose metabolism:

Liver

Lactating mammary gland

Other aspects of metabolism Amino-sugar synthesis Uronic acid pathway

Nucleotide sugars

Glycosyl donors in oligosacharide biosynthetic reactions (glycosyltransferases)

O – linked oligosacharides

N- linked oligosacharides

Interrelationships in aminosugar metabolism

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

1. Marks´ Basic Medical Biochemistry A Clinical Approach, third edition, 2009 (M.

Lieberman, A.D. Marks)

2. Textbook of Biochemistry with Clinical Correlations, sixth edition, 2006 (T.M. Devlin)

3. Meissenberg and Simmons: Principles of Medical Biochemistry, 3rd Edition, 2012

4.Voet, Voet and Pratt: Fundamentals of Biochemistry –Life at the molecular level 4th

Ed, 2013

5. Rodwell, V., Bender, D., et al.: Harpers Illustrated Biochemistry 30th Ed, 2015.

6. Salway, JG. Metabolism At a Glance 4th Edition, 2017