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METABOLISM OF CARBOHYDRATES:

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AMP stimulates phospho-fructokinase, whereas ATP and citrate inhibit it. Fructose 1,6-bisphosphatase is inhibited by AMP and activated by citrate. – PowerPoint PPT presentation

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Title: METABOLISM OF CARBOHYDRATES:


1
METABOLISM OF CARBOHYDRATES SYNTHESIS AND
DEGRADATION OF GLYCOGEN
2
GLYCOGEN SYNTHESIS AND DEGRADATION
In the well-fed state the glucose after
absorption is taken by liver and deposited as a
glycogen Glycogen is a very large, branched
polymer of glucose residues that can be broken
down to yields glucose molecules when energy is
needed
Most glucose residues in glycogen are linked by
a-1,4-glyco-sidic bonds, branches are created by
a-1,6-glycosidic bonds
3
Glycogen serves as a buffer to maintain
blood-glucose level.

Stable blood glucose level is especially
important for brain where it is the only fuel.

The glucose from glycogen
is readily mobilized and is therefore a good
source of energy for sudden, strenuous activity.
Liver (10 of weight) and skeletal muscles (2
) two major sites of glycogen storage Glycogen
is stored in cytosolic granules in muscle and
liver cells of vertebrates
4
Glucose-6-phosphate is the central metabolite in
the synthesis and decomposition of glycogen. In
the well-fed state glucose is converted to
glucose-6-phosphate, which is the precursor for
the glycogen synthesis. The glucose-6-phosphate
derived from the breakdown of glycogen has three
fates (1) glycolysis (2) pentose-phosphate
pathway (3) convertion to free glucose for
transport to another organs.
5
DEGRADATION OF GLYCOGEN
Glycogenolysis - degradation of glycogen The
reaction to release glucose from polysaccharide
is not simple hydrolysis as with dietary
polysaccharides but cleavage by inorganic
phosphate phosphorolytic cleavage Phosphorolyti
c cleavage or phosphorolysis is catalyzed by
enzyme glycogen phosphorylase There are two ends
on the molecules of starch or glycogen a
nonreducing end (the end glucose has free
hydroxyl group on C4) and a reducing end (the end
glucose has an anomeric carbon center (free
hydroxyl group on C1)
6
Glycogen phosphorylase removes glucose residues
from the nonreducing ends of glycogen Acts
only on a-1-4 linkages of glycogen polymer
Product is a-D-glucose 1-phosphate (G1P)
Cleavage of a glucose residue from the
nonreducing end of glycogen
7
Structure of glycogen phosphorylase (GP)
  • GP is a dimer of identical subunits (97kD each)
  • Catalytic sites are in clefts between the two
    domains of each subunit
  • Binding sites for glycogen, allosteric effectors
    and a phosphorylation site
  • Two forms of GP
  • Phosphorylase a (phospho- rylated) active
    form
  • Phosphorylase b (dephospho- rylated) less
    active

8
  • GP catalyzes the sequential removal of glucose
    residues from the nonreducing ends of glycogen
  • GP stops 4 residues from an a 1-6 branch point
  • Tranferase shifts a block of three residues from
    one outer branch to the other
  • A glycogen-debranching enzyme or 1,6-glucosidase
    hydrolyzes the 1-6-glycosidic bond
  • The products are a free glucose-1-phosphate
    molecule and an elongated unbranched chain

9
Metabolism of Glucose 1-Phosphate (G1P)
  • Phosphoglucomutase catalyzes the conversion of
    G1P to glucose 6-phosphate (G6P)

10
Glycogen Synthesis
  • Synthesis and degradation of glycogen require
    separate enzymatic steps
  • Cellular glucose converted to G6P by hexokinase
  • Three separate enzymatic steps are required to
    incorporate one G6P into glycogen
  • Glycogen synthase is the major regulatory step

11
Glucose 1-Phosphate formation
  • Phosphoglucomutase catalyzes the conversion of
    glucose 6-phosphate (G6P) to glucose 1-phosphate
    (G1P).

12
UDP-glucose is activated form of
glucose. UDP-glucose is synthesized from
glucose-1-phosphate and uridine triphosphate
(UTP) in a reaction catalized by UDP-glucose
pyrophosphorylase
13
Glycogen synthase adds glucose to the nonreducing
end of glycogen
14
A branching enzyme forms ?-1,6-linkages
Glycogen synthase catalyzes only
?-1,4-linkages. The branching enzyme is required
to form ?-1,6-linkages. Branching is
important because it increases the solubility of
glycogen. Branching creates a large number of
terminal residues, the sites of action of
glycogen phosphorylase and synthase.
15
Regulation of Glycogen Metabolism
  • Muscle glycogen is fuel for muscle contraction
  • Liver glycogen is mostly converted to glucose for
    bloodstream transport to other tissues
  • Both mobilization and synthesis of glycogen are
    regulated by hormones
  • Insulin, glucagon and epinephrine regulate
    mammalian glycogen metabolism

16
Hormones Regulate Glycogen Metabolism
Insulin
  • Insulin is produced by b-cells of the pancreas
    (high levels are associated with the fed state)
  • Insulin increases rate of glucose transport into
    muscle, adipose tissue via GluT4 transporter
  • Insulin stimulates glycogen synthesis in the
    liver via the second messenger phosphatidylinosito
    l 3,4,5-triphosphate (PIP3)

17
Glucagon
  • Secreted by the a cells of the pancreas in
    response to low blood glucose (elevated glucagon
    is associated with the fasted state)
  • Stimulates glycogen degradation to restore blood
    glucose to steady-state levels
  • Only liver cells are rich in glucagon receptors
    and therefore respond to this hormone

18
Epinephrine (Adrenalin)
  • Released from the adrenal glands in response to
    sudden energy requirement (fight or flight)
  • Stimulates the breakdown of glycogen to G1P
    (which is converted to G6P)
  • Increased G6P levels increase both the rate of
    glycolysis in muscle and glucose release to the
    bloodstream from the liver and muscles
  • Both liver and muscle cells have receptors to
    epinephrine

19
Effects of hormones on glycogen metabolism
20
Reciprocal Regulation of GlycogenPhosphorylase
and Glycogen Synthase
  • Glycogen phosphorylase (GP) and glycogen synthase
    (GS) control glycogen metabolism in liver and
    muscle cells
  • GP and GS are reciprocally regulated both
    covalently and allosterically (when one is active
    the other is inactive)
  • Covalent regulation by phosphorylation (-P) and
    dephosphorylation (-OH)
  • Allosteric regulation by glucose-6-phosphate (G6P)

21
Reciprocal Regulation of GP and GS
COVALENT REGULATION Active form a
Inactive form b Glycogen phosphorylase -P
-OH Glycogen synthase -OH -P
  • ALLOSTERIC REGULATION by G6P
  • GP a (active form) - inhibited by G6P
  • GS b (inactive form) - activated by G6P

22
Activation of GP and inactivation of GS by
Epinephrine and Glucagone
23
Activation of GS and inactivation of GP by Insulin
24
Gluconeo- genesis
Carbohydrates provide a significant portion of
human caloric intake
25
All cells are dependent on glucose. Glucose
level in blood plasma must be stable. Brain is
especially sensitive to the decrease of glucose
level (the daily glucose requirement of the brain
in a typical adult human being is about 120 g).
Red blood cells use only glucose as a fuel.
160 g of glucose needed daily by the whole body.
The amount of glucose present in body fluids is
about 20 g, and that readily available from
glycogen is approximately 190 g. During period
of fasting glycogen in liver is mobilized but it
only lasts 12 to 24 hours and this source of
glucose may not fulfill metabolic need. During
a longer period of starvation organism must
synthesize glucose from smaller noncarbohydrate
precursor molecules.
26
Gluconeogenesis synthesis of glucose from
noncarbohydrate precursors
  • Liver and kidney are major sites of glucose
    synthesis
  • Main precursors lactate, pyruvate, glycerol and
    some amino acids
  • Under fasting conditions, gluconeogenesis
    supplies almost all of the bodys glucose
  • Gluconeogenesis universal pathway. It present
    in animals, microorganisms, plants and fungi
  • Plants synthesize glucose from CO2 using the
    energy of sun, microorganisms from acetate and
    propionate

27
Gluconeogenesis is not a Reversal Glycolysis
In glycolysis, glucose is converted into
pyruvate in gluconeogenesis, pyruvate is
converted into glucose. However, gluconeogenesis
is not a reversal of glycolysis. There are three
irreversible reactions in glycolysis catalyzed by
hexokinase, phosphofructokinase, and pyruvate
kinase.
1. Glucose ATP ? glucose-6-phosphate ADP
(hexokinase) ?G -8 kcal mol-1 3.
Fructose-6-phosphate ATP ? fructose-1,6-biphosph
ate ADP (phosphofructokinase) ?G
-5.3 kcal mol-1

10. Phosphoenolpyruvate ADP ?
pyruvate ATP (pyruvate kinase) ?G -4 kcal
mol-1
These three reactions must be bypassed in
gluconeogenesis
28
Bypassed Reactions in Gluconeogenesis
1. Phosphoenolpyruvate is formed from pyruvate by
way of oxaloacetate through the action of
pyruvate carboxylase and phosphoenolpyruvate
carboxykinase. Pyruvate CO2 ATP H2O ?
oxaloacetate ADP Pi 2H Oxaloacetate GTP
? phosphoenolpyruvate GDP CO2 2. Fructose
6-phosphate is formed from fructose
1,6-bisphosphate.
Enzyme
- fructose 1,6-bisphosphatase. Fructose
1,6-bisphosphate H2O ? fructose 6-phosphate
Pi 3. Glucose is formed by hydrolysis of glucose
6-phosphate in a reaction catalyzed by glucose
6-phosphatase. Glucose 6-phosphate H2O ?
glucose Pi
29
Gluconeogenesis The distinctive reactions are
shown in red.
30
Comparison of glycolysis and gluconeogenesis
31
Bypass I Pyruvate ? Phosphoenolpyruvate
The first step in gluconeogenesis is the
carboxylation of pyruvate to form oxaloacetate at
the expense of a molecule of ATP.
Enzyme pyruvate carboxylase is present only in
mitochondria.
Pyruvate is transported into mitochondria from
cytoplasm the part of pyruvate is formed in
mitochondria from amino acids.
Essential cofactor of pyruvate carboxylase is
biotin, which serves as a carrier of CO2.
Biotin-binding domain of pyruvate carboxylase
Structure of carboxybiotin
32
Pyruvate carboxylase is allosterically activated
by acetyl CoA.
Accumulation of acetyl CoA from fatty acid
oxidation signals abundant energy, and directs
pyruvate to oxaloacetate for gluconeogenesis.
Pyruvate carboxylase reaction
biotin
This reaction takes place in mitochondria matrix.
33
Oxaloacetate is polar molecule and can not pass
through the mitochondria membrane into cytoplasm
Therefore it is reduced
oxaloacetate NADH2 ? malate NAD Enzyme
malate dehydrogenase
Malate passes through the mitochondria membrane
into cytoplasm and again oxidized to oxaloacetate
(enzyme malate dehydrogenase)
malate
NAD ? oxaloacetate NADH2
Cytoplasmic oxaloacetate is decarboxylated to
phosphoenolpyruvate by phosphoenolpyruvate
carboxykinase
34
Phosphoenolpyruvate carboxykinase reaction
Reaction takes place in the cytosol. In
decarboxylation reaction GTP donates a phosphoryl
group. Oxaloacetate is simultaneously
decarboxylated and phosphorylated by
phosphoenolpyruvate carboxykinase. One molecule
of ATP and one molecule of GTP were spent to lift
pyruvate to the energy level of
phosphoenlpyruvate.
35
Mechanism of phosphoenolpyruvate carboxykinase
reaction
36
Bypass II Fructose 1,6-bisphosphate ? Fructose
6-phosphate
  • A metabolically irreversible reaction
  • The enzyme responsible for this step is fructose
    1,6-bisphosphatase
  • F1,6BPase is allosterically inhibited by AMP and
    fructose 2,6-bisphosphate (F2,6BP)

37
Bypass III Glucose 6-phosphate ? glucose
  • In most tissues, gluconeogenesis ends with the
    formation of glucose 6-phosphate (G-6P).
  • Glucose 6-phosphate, unlike free glucose, cannot
    diffuse out of the cell.
  • The generation of free glucose is controlled in
    two ways
  • enzyme responsible for the conversion of glucose
    6-phos-phate into glucose, glucose 6-phosphatase,
    is regulated
  • enzyme is present only in tissues whose metabolic
    duty is to maintain blood-glucose homeostasis
    liver and to a lesser extent kidney, pancreas,
    small intestine.

38
The final step in the generation of glucose does
not take place in the cytosol. G-6-P is
transported into the lumen of the endoplasmic
reticulum, where it is hydrolyzed by glucose
6-phosphatase, which is bound to the membrane.
Glucose 6-phosphatase reaction
39
Ca2-binding stabilizing protein is essential for
phosphatase activity. Glucose and Pi are then
shuttled back to the cytosol by transporters.
Generation of glucose from glucose 6-phosphate.
Several proteins play a role in the generation of
glucose. T1 transports G-6-P into the lumen of
the ER T2 and T3 transport Pi and glucose
respectively back into the cytosol. SP
Ca-binding protein.
40
The Net Reaction of Gluconeogenesis
2 Pyruvate 2 NADH 4 ATP 2 GTP 6 H2O ?
Glucose 2 NAD 4 ADP 2 GDP 6 Pi 2H
?G' -9 kcal mol-1
Six nucleotide triphosphate molecules are
hydrolyzed to synthesize glucose from pyruvate in
gluconeogenesis, whereas only two molecules of
ATP are generated in glycolysis in the conversion
of glucose into pyruvate. The extra cost of
gluconeogenesis is four high phosphoryl-transfer
potential molecules per molecule of glucose
synthesized from pyruvate.
41
Subcellular Locations of Gluconeogenic Enzymes
  • Gluconeogenesis enzymes are cytosolic except
  • (1) Glucose 6-phosphatase (endoplasmic reticulum)
  • (2) Pyruvate carboxylase (mitochondria)
  • (3) Phosphoenolpyruvate carboxykinase (cytosol
    and/or mitochondria)

42
Regulation of Gluconeogenesis
Gluconeogenesis and glycolysis are reciprocally
regulated - within a cell one pathway is
relatively inactive while the other is highly
active.
The amounts and activities of the distinctive
enzymes of each pathway are controlled. The
rate of glycolysis is determined by the
concentration of glucose. The rate of
gluconeogenesis is determined by the
concentrations of precursors of glucose.
43
AMP stimulates phospho-fructokinase, whereas ATP
and citrate inhibit it. Fructose
1,6-bisphosphatase is inhibited by AMP and
activated by citrate. Fructose 2,6-bisphosphate
strongly stimulates phospho-fructokinase 1 and
inhibits fructose 1,6-bisphosphatase. During
starvation, gluconeo-genesis predominates because
the level of F-2,6-BP is very low. High levels
of ATP and alanine, which signal that the energy
charge is high and that building blocks are
abundant, inhibit the pyruvate kinase. Pyruvate
carboxylase is activated by acetyl CoA and
inhibited by ADP.
ADP inhibits phosphoenol-pyruvate carboxykinase.
Gluconeogenesis is favored when the cell is
rich in biosynthetic precursors and ATP.
44
Regulation of the Enzymes Amount by Hormones
Hormones affect gene expression primarily by
changing the rate of transcription. Insulin,
which rises subsequent to eating, stimulates the
expression of phosphofructokinase and pyruvate
kinase. Glucagon, which rises during
starvation, inhibits the expression of these
enzymes and stimulates the production of
phosphoenolpyruvate carboxykinase and fructose
1,6-bisphosphatase. Transcriptional control in
eukaryotes is much slower than allosteric
control it takes hours or days in contrast with
seconds to minutes.
45
Precursors for Gluconeogenesis
  • Any metabolite that can be converted to pyruvate
    or oxaloacetate can be a glucose precursor
  • Major gluconeogenic precursors in mammals
  • (1) Lactate
  • (2) Most amino acids (especially alanine),
  • (3) Glycerol (from triacylglycerol hydrolysis)

46
Lactate
  • Glycolysis generates large amounts of lactate in
    active muscle
  • Red blood cells steadily produce lactate
  • Lactate produced by active skeletal muscle and
    erythrocytes is a source of energy for other
    organs
  • The plasma membranes of some cells, particularly
    cells in cardiac muscle, contain carriers that
    make them highly permeable to lactate and
    pyruvate.
  • Lactate and pyruvate diffuse out of active
    skeletal muscle into the blood and then into
    these permeable cells.
  • Once inside these well-oxygenated cells, lactate
    can be reverted back to pyruvate and metabolized
    through the citric acid cycle and oxidative
    phosphorylation to generate ATP.
  • The use of lactate in place of glucose by these
    cells makes more circulating glucose available to
    the active muscle cells.
  • Excess lactate enters the liver.

47
The Cori Cycle
Liver lactate dehydrogenase converts lactate to
pyruvate (a substrate for gluconeogensis) Glucose
produced by liver is delivered to peripheral
tissues via the bloodstream
Contracting skeletal muscle supplies lactate to
the liver, which uses it to synthesize glucose.
These reactions constitute the Cori cycle
48
Amino Acids
  • Carbon skeletons of most amino acids are
    catabolized to pyruvate or citric acid cycle
    intermediates
  • The glucose-alanine cycle(1) Transamination of
    pyruvate yields alanine which travels to the
    liver(2) Transamination of alanine in the liver
    yields pyruvate for gluconeogenesis(3) Glucose
    is released to the bloodstream

49
Gluconeogensis from Glycerol
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