Transcript ppt

Metabolism of saccharides
Pavla Balínová
Sources of glucose (Glc)
from food (4 hours after meal)
● from glycogen (from 4 to 24 hours after meal)
● from gluconeogenesis (days after meal, during
starvation)
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Figure was assumed from Devlin, T. M. (editor): Textbook of Biochemistry with Clinical
Correlations, 4th ed. Wiley-Liss, Inc., New York, 1997
Glycemia
• glucose concentration in the blood
• physiological range of fasting glycemia 3,3 – 5,6 mmol/L
• is regulated by hormones (insulin, glucagon, epinephrine,
kortisol, …)
Glucose can enter into cells:
a) by facilitative diffusion (GLUT 1 – 7)
• GLUT 1 – blood-brain barrier, erythrocytes
• GLUT 2 – liver, β-cells in pancreas
• GLUT 3 – neurons
• GLUT 4 – skeletal muscles, heart muscle, adipose tissue
b) by cotransport with Na+ ion (SGLT-1 and 2)
small intestine, kidneys
Figure was assumed from textbook: Devlin, T. M. (editor): Textbook of Biochemistry
with Clinical Correlations, 4th ed. Wiley-Liss, Inc., New York, 1997.
An effect of insulin on insulin-sensitive cells
Transport of Glc into cells is dependent on insulin
effect (GLUT-4) in the following tissues: skeletal and
heart muscle and adipose tissue
Figure is found on http://www.mfi.ku.dk/ppaulev/chapter27/Chapter%2027.htm
Metabolic pathways included in utilization of Glc
– glycolysis, pentose cycle, glycogen synthesis
Phosphorylation of glucose
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after enter into cell Glc is always phosphorylated to
form Glc-6-P
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enzyme hexokinase catalyzes esterification of Glc
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ATP is a donor of phosphate group!
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enzyme is inhibited by excess of Glc-6-P
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2 isoenzymes of hexokinase exist: hexokinase and
glucokinase
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hexokinase has a higher affinity to glucose than
glucokinase
Hexokinase vs. glucokinase
KM hexokinase = 0,1 mM
KM glucokinase = 10 mM
Figure is found on http://web.indstate.edu/thcme/mwking/glycolysis.html
Glycolysis
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substrate: Glc-6-P
product: pyruvate
function: source of ATP
subcellular location: cytosol
organ location: all tissues
regulatory enzymes: hexokinase/glucokinase,
6-phosphofructokinase-1 (main regulatory enzyme),
pyruvatekinase
Regulatory enzymes are activated by hormone insulin!
Glycolysis
Figure is found on http://web.indstate.edu/thcme/mwking/glycolysis.html
Production of ATP in glycolysis
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conversion of 1,3-bisphosphoglycerate to 3-phosphoglycerate
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conversion of phosphoenolpyruvate (PEP) to pyruvate
These reactions are examples of substrate level
phosphorylation!
Regulation of glycolysis
Regulatory enzymes
● Hexokinase – inhibited by Glc-6-P
● Glucokinase – activated by insulin
– inhibited by Fru-6-P
6-phosphofructokinase-1 (PFK-1)
– activated by insulin, ↑AMP / ATP
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- inhibited by ↑ ATP /AMP, citrate
Pyruvatekinase
– activated by insulin, Fru-1,6-bisP
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- inhibited by glucagon, ↑ ATP /AMP, acetyl-CoA
Pentose phosphate pathway
• substrate: Glc-6-P
• product: CO2, NADPH + H+
• function: gain of NADPH + H+, production of rib-5-P for
nucleotide synthesis, mutual conversions of
monosacharides
• subcellular location: cytosol
• organ location: all tissues
• regulatory enzyme: glucose 6-phosphate dehydrogenase
Pentose phosphate pathway – oxidative stage
produces rub-5-P
Figure is found on http://web.indstate.edu/thcme/mwking/pentose-phosphate-pathway.html
Pentose phosphate pathway – non-oxidative stage
includes interconversions of monosaccharides
Figure is found on http://web.indstate.edu/thcme/mwking/pentose-phosphate-pathway.html
Glycogen synthesis (glycogenesis)
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substrate: Glc-6-P
product: glycogen
function: glucose storage in the form of glycogen
cellular location: cytosol
organ location: especially in the liver and skeletal
muscles, other tissues have lower glycogen storage
• regulatory enzyme: glycogen synthase
Enzyme glycogen synthase is inhibited by phosphorylation
(glucagon in liver and epinephrine in muscles)!
Glycogen synthesis
• Glc-6-P → Glc-1-P
• Glc-1-P + UTP → UDP-Glc + PPi
Glycogen synthase catalyzes the
formation of (1→4) glycosidic bonds.
Branching (formation of (1→6)
glycosidic bonds) is performed by
enzyme amylo-(1,4 – 1,6)transglycosylase („branching enzyme“).
Figure is found on http://en.wikipedia.org/wiki/Glycogen
Metabolic pathways serving to
supplementation of Glc into the bloodstream –
glycogen degradation and gluconeogenesis
Glycogen degradation (glycogenolysis)
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substrate: glycogen
product: Glc-6-P
function: releasing of Glc from glycogen
subcellular location: cytosol
organ location: liver, skeletal muscles, but also other tissues
regulatory enzyme: glycogen phosphorylase
Enzyme glycogen phosphorylase is activated by phosphorylation which
is induced by hormones glucagon and epinephrine. Insulin inhibits
enzyme phosphorylation.
Glycogen degradation
Glycogen (n Glc) + Pi → Glc-1-P + glycogen (n - 1 Glc)
Enzyme glycogen phosphorylase catalyzes the cleavage of
1→4 bonds.
Enzyme amylo-1→6-glucosidase („debranching enzyme“)
cleaves 1→6 bonds.
Glc-1-P ↔ Glc-6-P phosphoglucomutase
Glc-6-P glucose-6-phophatase
(liver, kidneys, enterocytes)
Glc
Gluconeogenesis
• substrates: lactate, pyruvate, glycerol, amino acids –
Ala, Asp, Gln etc.
• product: glucose
• function: synthesis of Glc from non-sugar precursors
• subcellular location: mitochondrial matrix + cytosol
• organ location: liver + kidneys
• regulatory enzymes: pyruvate carboxylase and PEP
carboxykinase
Regulatory enzymes are activated by hormones glucagon
and cortisol. Insulin inhibits them.
Scheme of gluconeogenesis
Figure is found on http://web.indstate.edu/thcme/mwking/gluconeogenesis.html
Gluconeogenesis
Synthesis of PEP is divided into 2 steps:
• Pyr → matrix of mitochondria → Pyr is carboxylated to
oxaloacetate (OA) by pyruvate carboxylase
CH3-CO-COO- + CO2 + ATP → -OOC-CH2-CO-COO- + ADP + Pi
• OA is transported to the cytosol and decarboxylated to
PEP by PEP carboxykinase
-OOC-CH -CO-COO- +
2
GTP → PEP + CO2 + GDP
Synthesis of 1 mol Glc consumes 4 mol ATP and 2 mol GTP!
Figure was assumed from http://www.biochem.arizona.edu/classes/bioc462/462b/glycolysis.html
Regulation of gluconeogenesis
Hormones:
• activation: cortisol, glucagon, epinephrine
• inhibition: insulin
Enzyme pyruvate carboxylase
• activation: acetyl-CoA from β-oxidation of FA → source of ATP
Enzyme fructose-1,6-bisphosphatase
• activation: citrate, starvation
• inhibition: AMP, Fru-2,6-bisP
Enzyme glucose-6-phosphatase (in ER of liver, kidneys and
enterocytes !)
Cori cycle
Figure was assumed from http://web.indstate.edu/thcme/mwking/gluconeogenesis.html
Glucose-alanine cycle
Figure is found on http://web.indstate.edu/thcme/mwking/gluconeogenesis.html
Fructose metabolism
• Fru is a component of sucrose (Glc + Fru)
• part of Fru in converted to Glc in enterocytes:
Fru-6-P → Glc-6-P → Glc
• part of Fru is absorbed and it is transferred via blood
into liver:
Fru + ATP → Fru-1-P + ADP by enzyme fructokinase
• Fru-1-P is broken down to glyceraldehyde (GA) and
dihydroxyacetonephosphate (DHAP) by aldolase
• DHAP enters glycolysis and GA → glyceraldehyde-3-P →
glycolysis
Galactose metabolism
• Gal is a component of lactose (Glc + Gal)
• Gal is absorbed by the same mechanism in
enterocytes like Glc → liver
• Gal is phosphorylated in liver to form Gal-1-P:
Gal + ATP → Gal-1-P + ADP by enzyme galactokinase
• Gal-1-P is converted to UDP-Gal:
Gal-1-P + UTP → UDP-Gal + PPi by uridyltransferase
• UDP-Gal is used to lactose synthesis in mammary
gland during lactation
• epimerization of UDP-Gal to UDP-Glc → glycogen
synthesis / synthesis of glucuronic acid / glycoprotein
synthesis