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Oxidation of Pyruvate to Acetyl-CoA. Pyruvate formed in the cytosol transported into the mitochondrion Oxidatively decarboxylated to acetyl-CoA NADH produced, transferred to the respiratory chain. 1 mol glucose 2 mol NADH ~ 2 x 2,5 ATP Enzyme : Pyruvate Dehydrogenase complex - PowerPoint PPT Presentation
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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