Functions of Glycogen

7/29/2019 Functions of Glycogen

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FUNCTIONS OF GLYCOGEN

Glycogen synthesized and stored in cytosolic granules in the liver andmuscle.

Liver glycogen maintain blood glucose concentration within normal rangeduring early fasting.

Muscle glycogen fuel reserve for the synthesis of ATP during musclecontraction.

GLYCOGENOLYSIS

4 ENZYMATIC ACTIVITIES FOR EFFICIENT BREAKDOWN OF GLYCOGEN

- One to degrade glycogen- Two to remodel glycogen so it remains a substrate for degradation- One to convert the product of glycogen breakdown into a form suitable for

further metabolism.

Cleaves substrate by phosphorolysis addition of Pi

Product is Glucose 1-PO4

Sequential removal of glycosyl residues from non-reducing ends (the one withfree 4-OH groups)

Pi splits the glycosidic link between C-1 of terminal residue and C-4 of thenext residue.

Pi specifically:1. Cleaves the bond between C-1 carbon atoms and glycosidic

oxygen atom.2. Retains the alpha configuration.

GLYCOGENOLYSIS

PHOSPHOROLYTIC CLEAVAGE OF TERMINAL 1,4 GLYCOSIDIC BONDS ATNON-REDUCING END

REMOVAL OF BRANCHES BY A DEBRANCHING ENZYME has 2 enzymeactivitiesa.) Glucose 4:4 transferase ( [1-4] -> [1-4] glucan transferase) b.) Amylo 1,6 glucosidase


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SYNTHESIS OF UDP-GLUCOSE

FORMATION OF GLYCOGEN PRIMER

ELONGATION OF GLYCOGEN CHAINS (AMYLOSE CHAIN FORMATION)

FORMATION OF BRANCHES


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AMINO ACID CARBON SKELETONS

Amino acids, when deaminated, yield -keto acids that, directly or via

additional reactions, feed into major metabolic pathways (ex, Krebs Cycle).

Amino acids are groups into 2 classes, based on whether or not carbon

skeletons can be converted to glucose:


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Glucogenic

Ketogenic

Carbon skeletons ofglucogenicamino acids are degraded to:

Pyruvate or

A 4-C or 5-C intermediate of Krebs Cycle. These are precursors forgluconeogenesis.

Glucogenic amino acids are the major carbon source for gluconeogenesiswhen

glucose levels are low. They can also be catabolized for energy, or converted to

glycogen or fatty acids for energy storage.

Carbon skeletons ofketogenic amino acids are degraded to:

Acetyl-CoA, or

Acetoacetate

Acetyl CoA, and its precursor acetoacetate, cannot yield net production ofoxaloacetate, the gluconeogenesis precursor.

For every 2-C acetyl residue entering Krebs Cycle, 2C leave as CO2.

Carbon skeletons of ketogenic amino acids can be catabolized for energy in KrebsCycle, or converted to ketone bodies or fatty acids. They cannot be convertedto glucose.

The 3-C -keto acid pyruvate is produced from

alanine, cysteine, glycine, serine and threonine.Alanine deamination via Transaminase directly yields pyruvate.


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Serine is deaminated to pyruvate via Serine Dehydratase.Glycine, which is also product ofthreonine catabolism, is converted to serine by

a reaction involving tetrahydrofolate.

The 4-CKrebs Cycle intermediate oxaloacetate is produced from aspartate andaspargine.

Aspartate transamination yields oxaloacetate.Aspartate is also converted to fumarate in Urea Cycle.

Fumarate is converted to oxaloacetate in Krebs Cycle.

Aspargine loses the amino group from its R-group by hydrolysis catalyzed byAsparaginase. This yields aspartate, whichcan be converted to oxaloacetate. Ex., bytransamination.

The 4-C Krebs intermediate succinyl-CoA isproduced from isoleucine, valine andmethionine.

Propionyl-CoA, an intermediate on thesepathways, is also a product of -oxidation of fatty acids with an odd number of C atoms.


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Proprionyl-CoA is carboxylated to methymalonyl-CoA.A racemase yields the L-isomer essential to the subsequent reaction.

Methymalonyl-CoA Mutase catalyzes a molecular rearrangement: the branchedC chain of methymalonyl-CoA is converted to the linear C chain ofsuccinyl-CoA.

The carboxyl that is in ester linkage to the thiol of coenzyme A is shifted to an

adjacent carbon atom, with opposite shift of a hydrogen atom.

Coenzyme B12, a derivative ofvitamin B12 (cobalamin), is the prosthetic group ofMethymalonyl-CoA Mutase.

Methyl group transfers are also carried out by B12 (cobalamin) in mammaliancells.

Methy-B12, (methycobalamin), with a methyl axial ligand substituting for the

deoxyadenosyl moiety of coenzyme B12, is an intermediate of such transfers.

BRANCHED CHAIN AMINO ACIDS

Branched chain amino acids initially share in part a common pathway.Branched Chain -Keto Acid Dehydrogenase (BCKDH) is a multi-subunitcomplex homologous to Pyruvate Dehydrogenase complex.

Genetic deficiency of BCKDH is called Maple Syrup Urine Disease (MSUD).


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High concentrations of branched chain keto acids urine give it a characteristic odor.

The 5-C Krebs Cycleintermediate -

ketoglutarate isproduced fromarginine,glutamate,glutamine,histidine andproline.

Glutamatedeamination via

Transaminase directlyyielding -

ketoglutarate.

Glutamate deamination by Glutamate Dehydrogenasealso directly yields -ketoglutarate.

THF exists in various forms, with single-C units ofvarying oxidation state, bonded at N5 or N10,

or bridging between them.

In these diagrams N10 with R is -aminobenzoic acid,linked to a chain of glutamate residues.

The cellular pool of THF includes various forms,produced and utilized in different reactions.


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N3-formimino-THF is involved in the pathway for degradation of histidine.Reactions using THF as donor of a single-C unit include synthesis of thymidylate,

methionine,f-methionine-tRNA, etc.

In the pathway ofhistidine degradation,N-formiminoglutamate is converted to glutamate bytransfer of the formimino group to THF,yielding N5-formimino-THF.

Histidine is first converted to glutamate. The last step in this pathway involvesthe cofactor tetrahydrofolate. Tetrahydrofolate (THF), which has a pteridine ring,

is a reduced form of the B vitamin folate.

Within a cell, THF has an attached chain of several glutamate residues, linked toone another by isopeptide bonds involving the R-group carboxyl.

AROMATIC AMINO ACIDS

Aromatic amino acids phenylalanine and tyrosine are catabolized to fumarateand acetoacetate.


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Hydroxylation ofphenylalanine to form tyrosine involves the reductanttetrahydrobiopterin. Biopterine, like folate, has a pteridine ring.

Dihydrobiopterin is reduced to tetrahydrobiopterin by electron transfer from NADH.

Thus NADH is secondarily the e- donor for conversion of phenylalanine to tyrosine.

Tyrosine is a precursor for synthesis ofmelanins and of epinephrine andnorephinephrine. High [phenylalanine] inhibits

Tyrosine Hydroxylase, on the pathway forsynthesis of the pigment melanin from tyrosine.Individuals with phenylketonuria have light skinand hair color.

Pheylalanine Hydroxylase includes a non-heme iron atomand its active site.

X-ray crystallography has shown the following are ligands tothe iron atom: His N, Glu O & water O, (fe shown in spacefill &ligands in ball & stick).

O2, tetrahydropbiopterin, and the iron atom in the ferrous (Fe++)

oxidation state participate in the hydroxylation.

O2 is thought to react initially with the tetrahydropbiopterin toform a peroxy intermediate.

Genetic deficiency of Phenylalaline Hydroxylase leads to the diseasephenylketonuria.

Phenylalanine & phenylpyruvate (the product of phenylalanine deamination viatransaminase) accumulate in blood and urine. Mental retardation results unlesstreatment begins immediately after birth. Treatment consists oflimitingphenylalanine intake to levels barely adequate to support growth. Tyrosine, anessential nutrient for individuals with phenylketonuria, must be supplied in the diet.

Or methionine may be regenerated from homocysteineby methy transfer from N5-methyl-tetrahydrofolate,via an enzyme that uses B12 as prosthetic group.

Another pathway converts homocysteine to glutathione.


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In various reactions, S-adenosylmethionine (SAM) isa donor of diverse chemical groups including methylene,amino, ribosyl and aminoalkyl groups, and a source of53-deoxyadenosyl radicals.But SAM is best known as methyl group donor.

Examples:S-adenosylmethionine asmethyl group donor:

Methylation of bases intRNA

Methylation ofcystosine residues inDNA

Methylation ofnorepinephrine - >epinephrine

Conversion ofglycerophospholipidPhosphatidyl ethanolamine ->phosphatidylcholine via methyltransfer from SAM.

Enzymes involved in formationand utilization of S-adenosylmethionine are

particularly active in liver.

Liver has important roles insynthetic pathways involvingmethylation reactions and in regulation of blood methionine.

METHYL GROUP DONORS

Methyl group donors in synthetic reactions include:


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Methyl-B12 S-adenosylmethionine (SAM)

N5-methyl-tetrahydrofolate (N5-methyl-THF)

Documents

Functions of Glycogen