carbohydrate metabolism iii · •disorders of carbohydrate metabolism. glycogen catabolism getting...
TRANSCRIPT
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Carbohydrate
metabolism III
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Outline
• Glycogen catabolism
• Glycogen cynthesis
• Control of glycogen metabolism
• Metabolism of fructose, galactose and
mannose
• Biosynthesys of glucuronic acid
• Disorders of carbohydrate metabolism
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Glycogen Catabolism Getting glucose from storage (or diet)
-Amylase is an endoglycosidase
• It cleaves amylopectin or glycogen to maltose,
maltotriose and other small oligosaccharides
• It is active on either side of a branch point, but
activity is reduced near the branch points
• Debranching enzyme cleaves "limit dextrins"
• Note the 2 activities of the debranching
enzyme
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Glycogen is a polymer of glucose residues linked by
(14) glycosidic bonds, mainly
(16) glycosidic bonds, at branch points.
Glycogen chains and branches are longer than shown.
Glucose is stored as glycogen predominantly in liverand muscle cells.
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Metabolism of Tissue Glycogen
Digestive breakdown is unregulated - 100%!
• But tissue glycogen is an important energy
reservoir - its breakdown is carefully controlled
• Glycogen consists of "granules" of high Mw
• Glycogen phosphorylase cleaves glucose from
the nonreducing ends of glycogen molecules
• This is a phosphorolysis, not a hydrolysis
• Metabolic advantage: product is a sugar-P - a
"sort-of" glycolysis substrate
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Glycogen catabolismbreakdown
• Glycogen Phosphorylase catalyzes phosphorolytic cleavage of the (14) glycosidic linkages of glycogen, releasing glucose-1-phosphate as reaction product.
glycogen(n residues) + Pi
glycogen(n–1 residues) + glucose-1-P
• This phosphorolysis may be compared tohydrolysis:
• Hydrolysis: R-O-R' + HOH R-OH + R'-OH
• Phosphorolysis: R-O-R' + HO-PO32- R-OH + R'-O-PO3
2-
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Glycogen Phosphorylase (GP)
• Pyridoxal phosphate (PLP), a
derivative of vitamin B6, serves
as prosthetic group for GP.
• PLP is held at the active site by a
Schiff base linkage, formed by
reaction of the aldehyde of PLP
with the -amino group of a
lysine residue.
• In contrast to its role in other
enzymes, the phosphate of PLP
is involved in acid/base catalysis
by Phosphorylase.
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• A glycogen storage site on the surface of
the Phosphorylase enzyme binds the
glycogen particle.
• Given the distance between storage and
active sites, Phosphorylase can cleave
(14) linkages only to within 4 residues of
an (16) branch point.
• This is called a "limit branch".
Glycogen Phosphorylase
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Debranching enzyme
• Debranching enzyme has 2 independent active sites, consisting of residues in different segments of a single polypeptide chain:
• The transferase of the debranching enzyme transfers 3 glucose residues from a 4-residue limit branch to the end of another branch, diminishing the limit branch to a single glucose residue.
• The (16) glucosidase moiety of the debranching enzyme then catalyzes hydrolysis of the (16) linkage, yielding free glucose. This is a minor fraction of glucose released from glycogen.
• The major product of glycogen breakdown is glucose-1-phosphate, from Phosphorylase activity.
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Phosphoglucomutase
• catalyzes the reversible reaction:
glucose-1-phosphate glucose-6-phosphate
• serine -OH at the active site donates and accepts Pi.
• the bisphosphate is not released
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• Glucose-6-P may enter Glycolysis or (mainly in liver) be dephosphorylated for release to the blood.
• Liver Glucose-6-phosphatase catalyzes the following, essential to the liver's role in maintaining blood glucose: glucose-6-P + H2O glucose + Pi
• Most other tissues lack this enzyme.
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Glycogen Synthesis
Glucose units are activated for transfer by formation of sugar nucleotides
• What are other examples of "activation"?
– acetyl-CoA, biotin, THF,
• Leloir showed in the 1950s that glycogen synthesis depends on sugar nucleotides
• UDP-glucose pyrophosphorylase
– a phosphoanhydride exchange
– driven by pyrophosphate hydrolysis
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• Uridine diphosphate glucose (UDP-glucose) is the immediate precursor for glycogen synthesis.
• As glucose residues are added to glycogen, UDP-glucose is the substrate and UDP is released as a reaction product.
• Nucleotide diphosphate sugars are precursors also for synthesis of other complex carbohydrates, including oligosaccharide chains of glycoproteins, etc.
Glycogen Synthesis
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UDP-Glucose pyrophosphorylase
• UDP-glucose is formed from glucose-1-phosphate:
• glucose-1-phosphate + UTP UDP-glucose + PPi
• PPi + H2O 2 Pi
Overall:
glucose-1-phosphate + UTP UDP-glucose + 2 Pi
• Spontaneous hydrolysis of the ~P bond in PPi
(P~P) drives the overall reaction.
• Cleavage of PPi is the only energy cost for glycogen synthesis (one ~P bond per glucose residue).
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Glycogen Synthase
Forms -(1 4) glycosidic bonds in glycogen
• Glycogenin (a protein!) forms the core of a
glycogen particle
• First glucose is linked to a tyrosine -OH
• Glycogen synthase transfers glucosyl units
from UDP-glucose to C-4 hydroxyl at a
nonreducing end of a glycogen strand.
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• A glycosidic bond is formed between the anomeric C1 of the glucose moiety derived from UDP-glucose and the hydroxyl oxygen of a tyrosine side-chain of Glycogenin.
• UDP is released as a product.
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• Glycogen Synthase then catalyzes elongation
of glycogen chains initiated by Glycogenin.
• Question: Where would you expect to find
Glycogenin within a cell?
• Answer: Most of the Glycogenin is found
associated with glycogen particles (branched
glycogen chains) in the cytoplasm.
Glycogen Synthase
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Glycogen Synthase
• Glycogen Synthase catalyzes transfer of the glucose moiety of UDP-glucose to the hydroxyl at C4 of the terminal residue of a glycogen chain to form an
(1 4) glycosidic linkage:
glycogen(n residues) + UDP-glucose
glycogen(n +1 residues) + UDP
• A branching enzyme transfers a segment from the end of a glycogen chain to the C6 hydroxyl of a glucose residue of glycogen to yield a branch with an
(1 6) linkage.
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Control of Glycogen Metabolism
A highly regulated process, involving reciprocal control of glycogen phosphorylase and glycogen synthase
• GP allosterically activated by AMP and inhibited by ATP, glucose-6-P and caffeine
• GS is stimulated by glucose-6-P
• Both enzymes are regulated by covalent modification - phosphorylation
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Regulation of glycogene metabolism
• Both synthesis and breakdown of glycogen are spontaneous.
• If both pathways were active simultaneously in a cell, there would be a "futile cycle" with cleavage of one ~P bond per cycle (in forming UDP-glucose).
• To prevent such a futile cycle, Glycogen Synthase and Glycogen Phosphorylase are reciprocally regulated, by allosteric effectors and by phosphorylation.
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Regulation of GP
• Glycogen Synthase is allosterically activated by glucose-6-P (opposite of effect on GP).
• Thus Glycogen Synthase is active when high blood glucose leads to elevated intracellular glucose-6-P.
• It is useful to a cell to store glucose as glycogen when the input to Glycolysis (glucose-6-P), and the main product of Glycolysis (ATP), are adequate.
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Phosphorylation of GP and GS
Covalent control
• Edwin Krebs and Edmond Fisher showed
in 1956 that a "converting enzyme"
converted phosphorylase „b“ to
phosphorylase „a“ (P)
• Nine Ser residues on GS are
phosphorylated!
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Enzyme Cascades and
GP/GS Hormonal regulation
• Hormones (glucagon, epinephrine)
activate adenylyl cyclase
• cAMP activates kinases and phosphatases
that control the phosphorylation of GP and
GS
• GTP-binding proteins (G proteins) mediate
the communication between hormone
receptor and adenylyl cyclase
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Hormonal Regulation II
Glucagon and epinephrine
• Glucagon and epinephrine stimulate glycogen
breakdown - opposite effect of insulin!
• Glucagon (29 res) is also secreted by pancreas
• Glucagon acts in liver and adipose tissue only!
• Epinephrine (adrenaline) is released from
adrenal glands
• Epinephrine acts on liver and muscles
• The phosphorylase cascade amplifies the
signal!
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Epinephrine and Glucagon
The difference...
• Both are glycogenolytic but for different
reasons!
• Epinephrine is the fight or flight hormone
– rapidly mobilizes large amounts of energy
• Glucagon is for long-term maintenance of
steady-state levels of glucose in the blood
– activates glycogen breakdown
– activates liver gluconeogenesis
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• Signal
cascade by
which
Glycogen
Phosphorylase
is activated.
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Hormonal Regulation
of Glycogen Synthesis and Degradation
• Insulin is secreted from the pancreas (to
liver) in response to an increase in blood
glucose
• Note that the portal vein is the only vein in
the body that feeds an organ!
• Insulin stimulates glycogen synthesis and
inhibits glycogen breakdown
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Sources of Sugars
• Glucose: lactose (dairy products) and
sucrose (table sugar)
• Fructose: fruits and sucrose
• Galactose: lactose
• Mannose: polysaccharides and
glycoproteins
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Other Substrates for Glycolysis
Fructose, galactose, and mannose
• Fructose and mannose are routed into glycolysis by fairly conventional means.
• Galactose is more interesting - the Leloir pathway "converts" galactose to glucose
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Metabolism of fructose
• Source - food – (saccharose, free)
• Synthese in cels – reduction of glucose
sorbitol oxidation fructose
• Metabolism occures in the liver (faster
than glucose – fructokinase have higher
activity)
• Target – glycolyse
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Sucrose(Table Sugar)
O- -D-Glucopyranosyl-(1—>2)- -D-Fructofuranoside
Sucrose -D-glucose + -D-fructosea-Glucosidase(Invertase)
Glycolysis
Mutarotation
-D-fructose
All Tissues
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Muscle Metabolism of Fructose(Anaerobic Glycolysis)
Large Amounts of Hexokinase
• Formation fructose-6-P (muscle) alternative wayphosphorylation - limited, because activity ofhexokinase is 1/20 from activity for glucose
• Minority alternative way – reduction fructose to sorbitolproduce glucose
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Liver Metabolism of Fructose I(Little Hexokinase)
• Obvious way transformation is fosforylation in the liver (partially in intestine epithel and in kidney)
• Fosforylation can not effect hunger or insulinecompensate glucose for diabetics
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Liver Metabolism of Fructose II
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Liver Metabolism of Fructose III
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Fructose Intolerance
• Too Much Fructose
–Fructose-1-P Aldolase is rate-limiting
–Depletion of Pi
–Reduction in [ATP]
– Increase in glycolysis
–Accumulation of lactate (acid) in blood
• Fructose-1-P Aldolase Deficiency (Genetic Disease)
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Metabolism of galactose
• Source - lactose
• Occures in the liver
• Galactose is necessary for synthesis of lactose, glycolipids, protheoglycans, glycoprotheins or can converted to glucose
• UDP-galactose is high energy molecules, galactose have ability bounded to other saccharides(-OH compound) and formed O-glycosidic bound (syntheseglycosaminoglycanes, glycoproteines, glycolipides)
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Lactose Metabolism(Dairy Products)
• Mutarotation of β-D-Galactose
• Glycolytic Enzymes are specific and do not
recognize galactose!
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Phosphorylation of Galactose
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Activation of Galactose
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Epimerization of UDP-Galactose
• Glycoproteins
• Glycolipids
Why UDP-Galactose?
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Metabolism of manose
• Minority part of diet
• Important part of glycoproteines
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The Role of Glucuronic acid
• Uridine-1-diphospho glucose can be used for:
• biosynthesis of glycogen
• biosynthesis of galactose
• after the oxidation at the 6th carbon atom is formed UDP-
glucuronic acid, which is used for:
• conjugation (bilirubine etc.)
• biosynthesis of glycosaminoglycanes (hialuronic acid,
heparin)
• biosynthesis of several pentoses (xylose, L-xylulose)
• biosynthesis of ascorbic acid
• Products capable be transformed in phosphopentose
pathway:
Glucuronate pathway Phosphopentose pathway
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Synthesis of
glucuronic acid
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Transformation of glucose-6-P
Glc-6-P Glucose (55 %)
Fru-6-PGlucosamine
(aminosaccharides)
Glycolysis (25 %)Glc-1-P
Glycogene (18 %)Glucuronate
Gulonate (vit. C)
6-P-Gluconate (2 %)
Penthose cycle
fosfatase
isomerase
mutasedehydrogenase
UTP
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