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Carbohydrate

metabolism III


Outline

Glycogen catabolism

Glycogen cynthesis

• Control of glycogen metabolism

• Metabolism of fructose, galactose and

mannose

• Biosynthesys of glucuronic acid

• Disorders of carbohydrate metabolism


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


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 liver

and muscle cells.


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 M w

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


Glycogen catabolism

breakdown

Glycogen Phosphorylase catalyzes

phosphorolytic cleavage of the (14)

glycosidic linkages of glycogen, releasing

glucose-1-phosphate as reaction product.

glycogen (n residues)

+ P i

glycogen (n–1 residues)

+ glucose-1-P

• This phosphorolysis may be compared to

hydrolysis:

• Hydrolysis: R-O-R' + HOH R-OH + R'-OH

• Phosphorolysis: R-O-R' + HO-PO 3

2-

R-OH + R'-O-PO 3

2-


Glycogen Phosphorylase (GP)

• Pyridoxal phosphate (PLP), a

derivative of vitamin B 6

, 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.


Glycogen Phosphorylase

• 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".


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.


Phosphoglucomutase

• catalyzes the reversible reaction:

glucose-1-phosphate glucose-6-phosphate

• serine -OH at the active site donates and accepts P i .

• the bisphosphate is not released


• 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 + H 2

O glucose + P i

• Most other tissues lack this enzyme.


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


Glycogen Synthesis

• 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.


UDP-Glucose pyrophosphorylase

• UDP-glucose is formed from glucose-1-phosphate:

• glucose-1-phosphate + UTP UDP-glucose + PP i

• PP i

+ H 2

O 2 P i

Overall:

glucose-1-phosphate + UTP UDP-glucose + 2 P i

• Spontaneous hydrolysis of the ~P bond in PP i

(P~P) drives the overall reaction.

• Cleavage of PP i

is the only energy cost for glycogen

synthesis (one ~P bond per glucose residue).


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.


• 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.


Glycogen Synthase

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

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.


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


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.


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.


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!


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


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!


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


• Signal

cascade by

which

Glycogen

Phosphorylase

is activated.


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


Sources of Sugars

• Glucose: lactose (dairy products) and

sucrose (table sugar)

• Fructose: fruits and sucrose

• Galactose: lactose

• Mannose: polysaccharides and

glycoproteins


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


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


Sucrose

(Table Sugar)

O- -D-Glucopyranosyl-(1—>2)- -D-Fructofuranoside

Sucrose -D-glucose + -D-fructose -D-fructose

a-Glucosidase

Mutarotation

(Invertase)

Glycolysis

All Tissues


Muscle Metabolism of Fructose

(Anaerobic Glycolysis)

Large Amounts of Hexokinase

• Formation fructose-6-P (muscle) alternative way

phosphorylation - limited, because activity of

hexokinase is 1/20 from activity for glucose

• Minority alternative way – reduction fructose to sorbitol

produce glucose


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 insuline

compensate glucose for diabetics


Liver Metabolism of Fructose II


Liver Metabolism of Fructose III


Fructose Intolerance

• Too Much Fructose

– Fructose-1-P Aldolase is rate-limiting

– Depletion of P i

– Reduction in [ATP]

– Increase in glycolysis

– Accumulation of lactate (acid) in blood

• Fructose-1-P Aldolase Deficiency

(Genetic Disease)


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 (synthese

glycosaminoglycanes, glycoproteines,

glycolipides)


Lactose Metabolism

(Dairy Products)

• Mutarotation of β-D-Galactose

• Glycolytic Enzymes are specific and do not

recognize galactose!


Phosphorylation of Galactose


Activation of Galactose


Epimerization of UDP-Galactose

Why UDP-Galactose?

• Glycoproteins

• Glycolipids


Metabolism of manose

• Minority part of diet

• Important part of glycoproteines


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 UDPglucuronic

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


Synthesis of

glucuronic acid


Transformation of glucose-6-P

fosfatase

Glc-6-P Glucose (55 %)

isomerase

dehydrogenase

mutase

6-P-Gluconate (2 %)

Fru-6-P

Glc-1-P

Glucuronate

UTP

Glucosamine

(aminosaccharides)

Glycolysis (25 %)

Glycogene (18 %)

Penthose cycle

Gulonate (vit. C)

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