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METABOLISM OF CARBOHYDRATES 5
web
József Mandl
2017
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Entry of glucogenic substrates
into gluconeogenesis
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glucoseG-6P
F-6Pfructose-1,6bisP
glyceraldehide-3P + diOH-aceton-P
1,3-bisphospho-glycerate
3P-glycerate
2P-glycerate
PEPpyruvate
F1,6bP-ase
G6P-ase
PEPCKPCOAA
alanine,
lactateglucoplastic
aminoacids
glycerin
glucose-1Pglycogen
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lactate
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Cori cycle
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glycerol
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trigliceride
glycerol
glycerol-3-P
dihydroxiacetone-P
lipase
glycerol
kinase
glycerol-3-P
dehydrogenase
Fatty cids
H2O
adipocyte
hepatocyte
blood
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Digestion of carbohydrates
• Mouth salivary amylase α(1-4) glycosidic
linkages are hydrolysed (starch, glycogen
– to maltose, glucose, oligosaccharides)
• Small intestine, duodenum
pancreatic amylase β(1-4) linkages
(cellulose) are not digested
sucrase, maltase, lactase, isomaltase
Glucose, fructose, galactose
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α-amylase
dextrinase
Enzymic hydrolysis of α1→4 and α1→6 glycosidic linkages in intestinal
lumen
maltase
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glucosegalactose
lactose sucrose
fructose
Glucose, fructose and galactose:
main monosacharides ingested
maltose
starch
glycogen
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Lactose intolerance – deficiency of lactase
Decrease in lactase is normal during development, declines to
about 5-10% of the level at birth
Milk sugar
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Fructose, galactose
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baso-
lateral
membrane
apical
membr.
ATP
ADP
+Pi
K+
Na+ K+glucose or
galactose
GLUT2
Na+
Na+
glucose or
galactose
glucose or
galactose
SGT
fructose
GLUT5
fructose
fructose
GLUT5GLUT2
Intestinal absorption of fructose and galactose
intestinal
lumen
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glucose
galactose
fructose
glucose
fructose
glucose-6-phosphate
glucose-6-phosphate
galactose-1-phosphate
fructose-1-phosphate
fructose-6-phosphate
ATP ADP
ATP ADP
ATP ADP
ATP ADP
ATP ADP
HEXOKINASE
FRUCTOKINASE
GALACTOKINASE
GLUCOKINASE
LIVER, KIDNEY, INTESTINE
OTHER TISSUES
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Fructose consumption in U.S.
• 1900 15 g/day (4% of total calories) –
fruits, vegetables
• 1939 24 g/day
• 1994 55 g/day (10%)
• 2010 73 g/day (12%) – sweetener industry
– juice intake
Ethanol and fructose (sucrose) – „civilisation
diet” – obesity epidemy, childhood obesity
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NADPH
+ H+ NADP+
NADH
+ H+NAD+
aldose reductase sorbitol
dehydrogenase
Polyol pathway
glucose sorbitol
(glucitol)
fructose
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Hardly controlled NADH and acetyl-CoA production leads to
enhanced triglyceride (fat) and cholesterol synthesis in the liver.
Fructose consumption is now considered as a risk factor of obesity
and the metabolic syndrome.
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fructose
fructose-1-phosphate
diOH-acetone-P
glyceraldehyde
glycerolglycerol-3-P
fructokinase
aldolase B
alcohol
DH
glycerol kinase
glycerol-3P
DH
ADP ATP
NAD+
NADH + H+
ATP
ADP
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aldolase B
(fructose-1-P aldolase)
fructose-1-phosphate
dihydroxyacetone-P
glyceraldehyde
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fructose-1,6-bisphosphate
dihydroxyacetone-P
glyceraldehyde-3P
aldolase A
(in glycolysis)
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glucoseglucose-6P
fructose-6Pfructose-1,6bisP
glyceraldehyde-3P + diOH-acetone-P
1,3-bisphospho-glycerate
3P-glycerate
2P-glycerate
PEPpyruvatePK-L
PFK1
GK
fructose
fructose-1-P
glyceraldehyde
glicerolglycerol-3-P
FK
aldolase
B
alcohol
DH
glycerol kinase
glycerol-3P
DH
main point of
regulation
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liver
F-1,6 -bisP
F-6-P
Essential
fructosuria
Congenital fructose
intolerance
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fructose
fructose-1-phosphate
diOH-acetone-P + glyceraldehyde
FK
aldolase B
ATP
ADP
Essential fructosuria
XX
accumulates in
blood after
meals
metabolized in
other tissues
and secreted
into urine
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Regulation of activity of glucokinase
R
Gk glucokinase
regulator protein binds to
Inactive Gk
Gk
F- 6 - P
inactive
Gk
RF- 6 - P binds to R complex
G-6-P does not bind to R
F - 1 - P
ActiveGk
F-1-P binds to R
R
Gk
Prevents binding to Gk
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fructose
fructose-1-phosphate
diOH-acetone-P + glyceraldehyde
FK
aldolase B
ATP
ADP
sustained ATP
and Pi depletion
glycogen
phosphorylase ↓↓
glucokinase ↑↑
pyruvate kinase ↑↑
glucose synthesis
blocked,
glycolysis activated
severe abdominal distress,
nausea, vomiting, hypoglycemia
and hyperuricemia after
fructose consumption;
liver damage in the long run,
gout, renal failure.
Fructose intolerance
XX
Fructokinase is expressed
in liver, kidney and small intestine.
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Intestinal absorption and cellular uptake of fructose are passive facilitated
diffusion mediated by GLUT2 and GLUT5.
Fructose is catabolized in two pathways:
- major pathway in liver, kidney and small intestine,
- minor pathway in all other tissues.
Fructose is a lipogenic sugar: enhances lipid synthesis and storage while
does not increase blood sugar (glucose) level.
Fructose is also synthesized (from glucose) in certain cells (e.g. epithelial
cells of lens and seminal vesicle).
Inborn defects of fructose metabolism:
- essential fructosuria (mild),
- fructose intolerance (severe).
Summary
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Galactose – glucose interconversion
liver
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galactose galactose-1P
UDP-glucose
UDP-galactose
glucose-1P
galactokinase
UDP-glucose:galactose-1P
uridyltransferase
4-epimerase
(NAD+)
ATP ADP
glucose-6P
phospho-
glucomutase
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Genetic deficiency:
GalactosemiaVomitus, diarrhea after
Milk, hepatomegaly,
Cirrhosis,
mental retardation
Reversible
Essential for
biosynthesis
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Accumulated in lens - cataract
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Type Defective enzyme
Type 1 galactose-1-phosphate uridyltransferase „classic galactosemia”
Type 2 galactokinase
Type 3 UDP-galactose 4-epimerase
Galactosemia: inborn defect of galactose metabolism
Accumulation of intermediates
of galactose metabolism (e.g.
galactose-1P, galactitol) causes
damages in various tissues.
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glucoseglucose-6P
fructose-6Pfructose-1,6bisP
glyceraldehyde-3P + diOH-acetone-P
1,3-bisphospho-glycerate
3P-glycerate
2P-glycerate
PEPpyruvatePK-L
PFK1
GK
G6Pase
glucose-1Pgalactosephospho-
glucomutase
glycogen
Galactose is equivalent with glucose
in the liver, kidney and small intestine.
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Intestinal absorption of galactose is a secondary active transport. Its
cellular uptake is passive facilitated diffusion mediated by GLUT
transporters.
Galactose is catabolized mostly in the liver.
Galactose is equivalent with glucose. It can be readily converted to blood
sugar (glucose).
Galactose is not essential because the cells possess 4-epimerase (e.g.
lactating mammary gland can synthesize lactose from glucose).
Inborn defects of galactose metabolism:
- 3 types of galactosemia
Summary
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UDP-glucose, or
UDP-galactose
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Synthesis of lactose, glycoproteins
In mammary gland only
UDP-galactose + glucose lactose + UDPLactose synthase (galactosyl transferase), α-lactalbumin
present in most tissues modifier subunit in mamma
In several tissues glycoprotein synthesis
UDP-galactose + N-acetylglucosaminegalactosyl transferase
N-acetyllactosamine + UDPglycoproteins
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glucose-1-phosphate
lactose
glucose glucose-6-phosphateglucose
Synthesis of lactose in lactating mammary gland
lactose
synthase
phospho-
glucomutase
hexokinase
GLUT1/3
UDP-glucose
pyrophosphorylase
blood cytosol
ATP ADP
UDP
UDP-glucose
PPi
UTP
UDP-galactose
4-epimerase
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