Oxidation of Pyruvate to Acetyl-CoA

Oxidation of Pyruvate to Acetyl-CoAPyruvate formed in the cytosol transported into the mitochondrion Oxidatively decarboxylated to acetyl-CoANADH produced, transferred to the respiratory

chain.o 1 mol glucose 2 mol NADH ~ 2 x 2,5 ATPo Enzyme : Pyruvate Dehydrogenase complexo Pyruvate dehydrogenase component inhibited

by NADH and Acetyl-CoA.o Deficiency of B1 vitamin beri-beri

Pyruvate is decarboxylated by the pyruvate dehydrogenase component of the enzyme complex to a hydroxyethyl derivative of the thiazole ring of enzyme-bound thiamin diphosphate, which in turn reacts with oxidized lipoamide, the prosthetic group of dihydrolipoyl transacetylase, to form acetyl lipoamide (Figure 18–5). Acetyl lipoamide reacts with coenzyme A to form acetyl-CoA and reduced lipoamide. The reaction is completed when the reduced lipoamide is reoxidized by a flavoprotein, dihydrolipoyl dehydrogenase, containing FAD. Finally, the reduced flavoprotein is oxidized by NAD+ , which in turn transfers reducing equivalents to the respiratory chain.Pyruvate + NAD+ + CoA Acetyl-CoA + NADH + H+ + CO2

Pyruvate dehydrogenase

Pyruvate Dehydrogenase Is Regulated by End-Product Inhibition & Covalent Modification

Pyruvate dehydrogenase is inhibited by its products, acetyl-CoA and NADH.

It is also regulated by phosphorylation by a kinase of three serine residues on the pyruvate dehydrogenase component of the multi enzyme complex, resulting in decreased activity and by dephosphorylation by a phosphatase that causes an increase in activity. The kinase is activated by increases in the [ATP]/[ADP], [acetyl-CoA]/[CoA], and [NADH]/[NAD+ ] ratios. Thus, pyruvate dehydrogenase, and therefore glycolysis, is inhibited both when there is adequate ATP available, and also when fatty acids are being oxidized.

Glycogen: Glycogenesis & glycogenolysis Energy storage as carbohydrate in the liver and muscle

In the liver up to 6 % w/w In the muscle up to 4 % w/w Fasting for 18 hours will depletes glycogen in the liver

In the muscle glycogen will never be depleted

Molecular mass up to 4 millions

GlycogenesisIn the fed state, glycogen synthesis

increaseGlucose 6P (some, not all) G 1P

(phosphoglucomutase)G 1P with UTP UDPG + PP (UDPG pyrophosphorylase)PP Pi drives the reaction to the right (pyrophosphatase)UDPG + glycogenn glycogenn+1 + UDP

(Glycogen Synthase = GS)UDP + ATP UTP + ADPGlycogen synthesis from glucose require two ATP

Pathways of glycogenesis and of glycogenolysis in the liver.

Amylo α(1-4) α(1-6)Transglucosidase)

Pathways of glycogenesis and of glycogenolysis in the liver.

GlycogenolysisDuring fasting(liver) or during contraction

(muscle)Glycogen cleavaged by phosphorylase and

debranching enzymesGlucose 1P ( G 1P ) and glucose are releasedPhosphate Pi is requiredIn the liver : G 1P G 6P (phosphogluco

mutase) G 6P G + Pi (glucose 6Pase)In the muscle : G 1P G 6P (phosphogluco mutase) G 6P enter glycolysis ATP

Glucose 6 Pase can only be found in the liver, intestine and kidney

Amylo α(1-4) α(1-4) Glucantransferase

Control of GlycogenolysisDuring fasting when blood glucose tend to decline, glucagon through protein G will activates adenylyl cyclase.

Adenylyl cyclase catalyzes formation of cAMP from ATP.

cAMP in turn activates cAMP Dependent Protein Kinase. Then it catalyzes Phosphorylase Kinase into PK-P

Phosphorylase Kinase-P (active = a) Phosphorylase Kinase-P (active = a) will catalyzes Phosphorylasewill catalyzes Phosphorylase(b=inactive) to Phosphorylase-P (a).(b=inactive) to Phosphorylase-P (a).The Phosphorylase-P will split The Phosphorylase-P will split Glycogen. Glucose 1P released Glycogen. Glucose 1P released (require Pi). Glucose 6 phosphatase (require Pi). Glucose 6 phosphatase hydrolysis G 6P to G and Pi.hydrolysis G 6P to G and Pi.Glucose enter the blood stream to Glucose enter the blood stream to stabilize blood Glucose.stabilize blood Glucose.

Epinephrine in muscle

If you are startled epinephrine in muscle

activates Adenylyl cyclase , catalyze ATP cAMP

cAMP Dependent PK active. Phosphorylase kinase active.

Phosphorylase active. Glycogen G 1P. G 6P no G 6Pase in the muscle, G 6P x G.

G 6P glycolysis ATPEye Central N.S Peripheral nerves Synapses

Ca++

Ca/Calmodulin phosphorylase kinase active etc.

Role of Ca++ in glycogenolysis

GlycogenesisGycogen Synthase ( GS ) active form GS,

and GS-P inactive form. Protein Kinase

GS GS-P

↑ GSK

There are seven Protein kinase that control glycogenesis

Ca++ / Calmodulin Dependent ( 1 phosphorylase kinase )

cAMP Dependent Protein kinaseGlycogen Synthase Kinase (GSK) 3, 4 and

5

Glycogenolysis in muscle increases several 100-fold at the onset of contraction; the same signal (increased cytosolic Ca2+ ion concentration) is responsible for

initiation of both contraction and glycogenolysis. Muscle phosphorylase kinase, which activates glycogen

phosphorylase, is a tetramer of four different subunits, α, β, γ, and δ. The α and β subunits contain serine

residues that are phosphorylated by cAMP-dependent protein kinase. The δ subunit is identical to the Ca2+ -

binding protein calmodulin, and binds four Ca2+ . The binding of Ca2+ activates the catalytic site of the subunit

even while the enzyme is in the dephosphorylated b state; the phosphorylated a form is only fully activated in

the presence of high concentrations of Ca2+ .

Protein Phosphatase-1

Protein Phosphatase-1 hydrolyzes protein-P to Protein Kinase and Pi .

Enzymes - P : Glycogen Synthase-P Phosphorylase-P Phosphorylase Kinase-P

Protein Phosphatase-1 is inhibited by Inhibitor 1-PInhibitor 1 Inhibitor 1-P its phosphorylation

catalyzed by cAMP Dependent PK.

The Control of Phosphorylase Differs between Liver & Muscle

In the Liver:Inhibited byATPG 6PGlucose

In the muscle :Inhibited by:ATPG 6PActivated by 5’AMP

Effect of Insulin:Phosphorylase is inhibited by glucose (in the liver) . Insulin inhibits Phosphorylase if G available.

If glucose concentration increases G 6P follows, in turn it will activates glycogen synthase

Insulin (+) GS-P GS Protein phosphatase-1

Epinephrine effects liver glycogenolysis through :

1.Its effects on glucagon released2.Beta-adrenergik receptor, in turn

cAMP formation etc.3.Alfa-adrenergic receptor

Inositol triphosphate (IP3), Ca++

exit from ER Phosphorylase kinase phosphorylase etc. ( The major mechanism of the three)

Type Ia glycogenosis ( von Gierke's disease ).Deficiency : glucose-6 phosphataseClinical features :Glycogen accumulation in liver and renal tubule

cells,hypoglycemia; lactic acidemia; ketosis;

hyperlipemia.

Glycogen Storage Diseases Are Inherited

Type V (Myophosphorlylase deficiency, McArdle's syndrome)Deficiency : Muscle phosphorylasePoor exercise tolerance; muscle glycogen abnormally high (2.5–4%); blood lactate very low after exercise

Type VI (Hers' disease)Deficiency : Liver phosphorylaseClinical features:Hepatomegaly; accumulation of glycogen in liver; mild hypoglycemia; generally good prognosis

Type VII (Tarui's disease)Deficiency : Muscle and erythrocyte phosphofructokinase 1Clinical features:Poor exercise tolerance; muscle glycogen abnormally high (2.5–4%); blood lactate very low after exercise; also hemolytic anemia