![Page 1: Metabolism of pentoses, glycogen, fructose and galactose Jana Novotna](https://reader036.vdocuments.us/reader036/viewer/2022062500/5697bfad1a28abf838c9bf24/html5/thumbnails/1.jpg)
Metabolism of pentoses, glycogen, fructose and galactose
Jana Novotna
![Page 2: Metabolism of pentoses, glycogen, fructose and galactose Jana Novotna](https://reader036.vdocuments.us/reader036/viewer/2022062500/5697bfad1a28abf838c9bf24/html5/thumbnails/2.jpg)
1. The Pentose Phosphate Pathway
![Page 3: Metabolism of pentoses, glycogen, fructose and galactose Jana Novotna](https://reader036.vdocuments.us/reader036/viewer/2022062500/5697bfad1a28abf838c9bf24/html5/thumbnails/3.jpg)
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).
![Page 4: Metabolism of pentoses, glycogen, fructose and galactose Jana Novotna](https://reader036.vdocuments.us/reader036/viewer/2022062500/5697bfad1a28abf838c9bf24/html5/thumbnails/4.jpg)
![Page 5: Metabolism of pentoses, glycogen, fructose and galactose Jana Novotna](https://reader036.vdocuments.us/reader036/viewer/2022062500/5697bfad1a28abf838c9bf24/html5/thumbnails/5.jpg)
An overview:
![Page 6: Metabolism of pentoses, glycogen, fructose and galactose Jana Novotna](https://reader036.vdocuments.us/reader036/viewer/2022062500/5697bfad1a28abf838c9bf24/html5/thumbnails/6.jpg)
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
![Page 7: Metabolism of pentoses, glycogen, fructose and galactose Jana Novotna](https://reader036.vdocuments.us/reader036/viewer/2022062500/5697bfad1a28abf838c9bf24/html5/thumbnails/7.jpg)
Regulation:
Glucose 6-phosphate dehydrogenase
• inhibition - by NADPH
• induction - by insulin/gluckagon ↑
1. The oxidative phase of PPP:
![Page 8: Metabolism of pentoses, glycogen, fructose and galactose Jana Novotna](https://reader036.vdocuments.us/reader036/viewer/2022062500/5697bfad1a28abf838c9bf24/html5/thumbnails/8.jpg)
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
![Page 9: Metabolism of pentoses, glycogen, fructose and galactose Jana Novotna](https://reader036.vdocuments.us/reader036/viewer/2022062500/5697bfad1a28abf838c9bf24/html5/thumbnails/9.jpg)
2. The nonoxidative phase of PPP:
![Page 10: Metabolism of pentoses, glycogen, fructose and galactose Jana Novotna](https://reader036.vdocuments.us/reader036/viewer/2022062500/5697bfad1a28abf838c9bf24/html5/thumbnails/10.jpg)
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
![Page 11: Metabolism of pentoses, glycogen, fructose and galactose Jana Novotna](https://reader036.vdocuments.us/reader036/viewer/2022062500/5697bfad1a28abf838c9bf24/html5/thumbnails/11.jpg)
The role of PPP in maintenance of the erythrocyte membrane integrity:
![Page 12: Metabolism of pentoses, glycogen, fructose and galactose Jana Novotna](https://reader036.vdocuments.us/reader036/viewer/2022062500/5697bfad1a28abf838c9bf24/html5/thumbnails/12.jpg)
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
![Page 13: Metabolism of pentoses, glycogen, fructose and galactose Jana Novotna](https://reader036.vdocuments.us/reader036/viewer/2022062500/5697bfad1a28abf838c9bf24/html5/thumbnails/13.jpg)
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
![Page 14: Metabolism of pentoses, glycogen, fructose and galactose Jana Novotna](https://reader036.vdocuments.us/reader036/viewer/2022062500/5697bfad1a28abf838c9bf24/html5/thumbnails/14.jpg)
2. Metabolism of glycogen
![Page 15: Metabolism of pentoses, glycogen, fructose and galactose Jana Novotna](https://reader036.vdocuments.us/reader036/viewer/2022062500/5697bfad1a28abf838c9bf24/html5/thumbnails/15.jpg)
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
![Page 16: Metabolism of pentoses, glycogen, fructose and galactose Jana Novotna](https://reader036.vdocuments.us/reader036/viewer/2022062500/5697bfad1a28abf838c9bf24/html5/thumbnails/16.jpg)
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
![Page 17: Metabolism of pentoses, glycogen, fructose and galactose Jana Novotna](https://reader036.vdocuments.us/reader036/viewer/2022062500/5697bfad1a28abf838c9bf24/html5/thumbnails/17.jpg)
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
![Page 18: Metabolism of pentoses, glycogen, fructose and galactose Jana Novotna](https://reader036.vdocuments.us/reader036/viewer/2022062500/5697bfad1a28abf838c9bf24/html5/thumbnails/18.jpg)
Glycogen metabolism - an overview:
Synthesis and degradation of glycogen:
→ different enzymes (regulation!)
![Page 19: Metabolism of pentoses, glycogen, fructose and galactose Jana Novotna](https://reader036.vdocuments.us/reader036/viewer/2022062500/5697bfad1a28abf838c9bf24/html5/thumbnails/19.jpg)
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).
![Page 20: Metabolism of pentoses, glycogen, fructose and galactose Jana Novotna](https://reader036.vdocuments.us/reader036/viewer/2022062500/5697bfad1a28abf838c9bf24/html5/thumbnails/20.jpg)
Glycogenin - (enzyme) initiates glycogen synthesis.
![Page 21: Metabolism of pentoses, glycogen, fructose and galactose Jana Novotna](https://reader036.vdocuments.us/reader036/viewer/2022062500/5697bfad1a28abf838c9bf24/html5/thumbnails/21.jpg)
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)
![Page 22: Metabolism of pentoses, glycogen, fructose and galactose Jana Novotna](https://reader036.vdocuments.us/reader036/viewer/2022062500/5697bfad1a28abf838c9bf24/html5/thumbnails/22.jpg)
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:
![Page 23: Metabolism of pentoses, glycogen, fructose and galactose Jana Novotna](https://reader036.vdocuments.us/reader036/viewer/2022062500/5697bfad1a28abf838c9bf24/html5/thumbnails/23.jpg)
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:
![Page 24: Metabolism of pentoses, glycogen, fructose and galactose Jana Novotna](https://reader036.vdocuments.us/reader036/viewer/2022062500/5697bfad1a28abf838c9bf24/html5/thumbnails/24.jpg)
Regulation of glycogen synthase by covalent modification
![Page 25: Metabolism of pentoses, glycogen, fructose and galactose Jana Novotna](https://reader036.vdocuments.us/reader036/viewer/2022062500/5697bfad1a28abf838c9bf24/html5/thumbnails/25.jpg)
Regulation of glycogen phosphorylase by covalent modification
![Page 26: Metabolism of pentoses, glycogen, fructose and galactose Jana Novotna](https://reader036.vdocuments.us/reader036/viewer/2022062500/5697bfad1a28abf838c9bf24/html5/thumbnails/26.jpg)
Regulation of glycogen synthesis and degradation in the liver
![Page 27: Metabolism of pentoses, glycogen, fructose and galactose Jana Novotna](https://reader036.vdocuments.us/reader036/viewer/2022062500/5697bfad1a28abf838c9bf24/html5/thumbnails/27.jpg)
Activation of muscle glycogen phosphorylase during exercise
![Page 28: Metabolism of pentoses, glycogen, fructose and galactose Jana Novotna](https://reader036.vdocuments.us/reader036/viewer/2022062500/5697bfad1a28abf838c9bf24/html5/thumbnails/28.jpg)
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
![Page 29: Metabolism of pentoses, glycogen, fructose and galactose Jana Novotna](https://reader036.vdocuments.us/reader036/viewer/2022062500/5697bfad1a28abf838c9bf24/html5/thumbnails/29.jpg)
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:
![Page 30: Metabolism of pentoses, glycogen, fructose and galactose Jana Novotna](https://reader036.vdocuments.us/reader036/viewer/2022062500/5697bfad1a28abf838c9bf24/html5/thumbnails/30.jpg)
Summary:
Glycogen metabolism Different role of glycogen stores in the liver and muscles Glycogen synthesis and degradation are separate pathways
(regulation) Glycogen storage diseases
![Page 31: Metabolism of pentoses, glycogen, fructose and galactose Jana Novotna](https://reader036.vdocuments.us/reader036/viewer/2022062500/5697bfad1a28abf838c9bf24/html5/thumbnails/31.jpg)
3. Fructose and Galactose metabolism
![Page 32: Metabolism of pentoses, glycogen, fructose and galactose Jana Novotna](https://reader036.vdocuments.us/reader036/viewer/2022062500/5697bfad1a28abf838c9bf24/html5/thumbnails/32.jpg)
Principally in the liver (small intestine, kidney)
Aldolase B: low affinity for fructose 1-phosphate (→ accumulation of fructose 1-phosphate in the liver )
Fructose metabolismEssential fructosuria
Hereditary fructose intolerance
![Page 33: Metabolism of pentoses, glycogen, fructose and galactose Jana Novotna](https://reader036.vdocuments.us/reader036/viewer/2022062500/5697bfad1a28abf838c9bf24/html5/thumbnails/33.jpg)
The polyol pathway
Seminal vesicles (spermatozoa use fructose)
Accumulation of sorbitol in diabetic patients Lens (diabetic cataract) Muscles, nerves (periferal neuropathy)
![Page 34: Metabolism of pentoses, glycogen, fructose and galactose Jana Novotna](https://reader036.vdocuments.us/reader036/viewer/2022062500/5697bfad1a28abf838c9bf24/html5/thumbnails/34.jpg)
Galactose metabolism:
![Page 35: Metabolism of pentoses, glycogen, fructose and galactose Jana Novotna](https://reader036.vdocuments.us/reader036/viewer/2022062500/5697bfad1a28abf838c9bf24/html5/thumbnails/35.jpg)
Lens metabolism:
Diabetic cataract :
↑glucose concentration in the lens → ↑aldose reductase activity → sorbitol accumulation → ↑osmolarity, structural changes of proteins
![Page 36: Metabolism of pentoses, glycogen, fructose and galactose Jana Novotna](https://reader036.vdocuments.us/reader036/viewer/2022062500/5697bfad1a28abf838c9bf24/html5/thumbnails/36.jpg)
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)
![Page 37: Metabolism of pentoses, glycogen, fructose and galactose Jana Novotna](https://reader036.vdocuments.us/reader036/viewer/2022062500/5697bfad1a28abf838c9bf24/html5/thumbnails/37.jpg)
Summary:
Fructose and Galactose metabolism Conversion to intermediates of glycolysis Genetic abnormalities, accumulation of intermediates, tissue
damage Accumulation of sorbitol in diabetes
![Page 38: Metabolism of pentoses, glycogen, fructose and galactose Jana Novotna](https://reader036.vdocuments.us/reader036/viewer/2022062500/5697bfad1a28abf838c9bf24/html5/thumbnails/38.jpg)
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)