Download ppt - Coordinated regulation of glycolysis/gluconeogenesis

Coordinated regulation of glycolysis/gluconeogenesis

High blood glucose

Synthesis of hexokinase II, PFK-1, pyruvate kinase

Movement of GLUT4 to plasma membrane of myocyte

Activation of insulin-sensitive protein kinase

Activation of protein kinase B

Insulin secretion

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Glu

cose

Pancreatic cellGLUT2

Glucose

Glucose

Glycolysispyruvate

Citric acid cycle

NADH,FADH2

ATP

Oxidative phosphorylation

ATP-gated K+ channel

K+

- - - - - - -- - - - - - -+ + + + + + +

+ + + + + + +

Membrane depolarization

closed

Voltage-dep. Ca2+ channelCa2+

OpenCa2+

Insulin secretion

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Glc

GlcGlc

Glc Glc

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Insulin receptor

Insulin

GLUT4

GlcGlc

Glc

Glc

Glc

Cytosol of myocyte

Movement of GLUT4 to plasma membrane of myocyte

Activation of insulin-sensitive kinasep. 588

Insulin receptor

Insulin

Insulin-sensitive

kinase

Insulin-sensitive

kinase

GM

GM

PP1PP1 Glycogen synthase aGlycogen synthase b

Phosphorylase kinase


Glycogen phosphorylase


Glycogen synthesis Glycogen degradation

Activation of protein kinase B (PKB)

Insulin receptor

Insulin

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IRS-1

GSK-3

IRS-1

PIP2

PIP3PI3-K PDK-1PI3-K PDK-1

GSK-3

GSK-3

Glycogen synthase aGlycogen synthase a

Glycogen synthase b

Glycogen synthesis

PKBPKB

GSK3 inactivate glycogen synthase by phosphorylation

PP

GSK3

P

GSK3

P

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Phosphorylation by Casein kinase II

PKB

GSK3 can be inactivated by phosphorylation

PP

p.587

FruGlc

Regulator protein

High blood glucose affect hexokinase IV activity

GLUT2Hexokinase

IV

nucleus

Regulator protein

Fru

Glc

Regulator protein

Hexokinase IV

Regulator protein

Fru

Hexokinase IV

Glc

Glc

Glc

Glc

Glc

Glc

Glc

Glc

Glc

Hepatocyte

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Insulin receptor

Insulin

Insulin regulate PFK-1 activity

Phosphoprotein phosphatase

Phosphoprotein phosphatase

PFK-2FBPase-2

PFK-2FBPase-2

Fru

F2,6BP

Fru

F6P

PFK-2FBPase-2

PFK-1PFK-1Fru

F1,6BP

Fru

F6PFBPase-1FBPase-1

Fru

F2,6BP

Low blood glucose

Inactivation of pyruvate kinase L (liver form)

Activation of FBPase-2 and inactivation of PFK-2

Inactivation of glycogen synthase

Activation of glycogen phosphorylase

Glucagon secretion

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Glucagon receptor

glucagon

GDP

GTP

Glucagon receptor

Adenylyl cyclase

Adenylyl cyclase

ATP

cAMP

Protein kinase AProtein kinase A

Regulation pathway initiated by glucagon secretion

GM

GM

PFK-2FBPase-2

PFK-2FBPase-2

Pyruvate kinase L

Pyruvate kinase L

Regulation of PFK-1 by glucagon

Protein kinase A

PFK-2FBPase-2

PFK-2FBPase-2

Protein kinase A

Fru

F2,6BP

Fru

F6PPFK-1PFK-1 FBPase-1

Fru

F2,6BP

FBPase-1Fru

F6P

Fru

F1,6BP

Regulation of glycogen synthesis and breakdown by glucagon

p. 588

PP1PP1 Glycogen synthase aGlycogen synthase b





Glycogen synthesis Glycogen degradation

GM

Protein kinase A

GM

Protein kinase A

Inhibitor-1

Inhibitor-1

Hexokinase

• There are four isozymes (I, II, III and IV) of hexokinase encoded by four different genes.

• Hexokinase I and II are allosterically inhibited by their product, glucose 6-phosphate. Hexokinase IV is not inhibited by G-6-P.

Hexokinase

• Hexokinase I and II are the predominant forms existing in muscle. Hexokinase IV is the predominant form in liver.

• Hexokinase I and II will be half-saturated at about 0.1mM, but hexokinase IV will not be half-saturated until 10mM.

Hexokinase

• Hexokinase has different functions in liver and muscle.

• Muscle consumes glucose, using it for energy production.

• Liver maintains blood glucose homeostasis by removing or producing glucose.

Muscle hexokinase

• Because blood glucose concentration is about 4 to 5 mM, hexokinase in the muscle (which will be half saturated at 0.1mM) is always working at or near its maximal rate.

Liver hexokinase

• However, liver hexokinase (half-saturated at 10mM) will not ever reach its maximal rate even after meal.

Phosphofructokinase-1

• PFK-1 catalyze the committing step of glycolysis.

• This enzyme is regulated by ATP, AMP, ADP, citrate and fructose 2,6-bisphosphate.

ATP regulate the affinity of PFK-1 towards its substrate F-6-P

• Not only as a substrate, ATP is also one of the end product of the glycolytic pathway.

• ATP inhibit PFK-1 by binding to an allosteric site and lowering the affinity of the enzyme for F-6-P.

Molecules regulate PFK-1 and FBPase-1 activity

• ADP and AMP relieve the inhibition by ATP.• Citrate increases the inhibitory effect of ATP.• F-2,6-BP is the strongest activator of PFK-1.

PFK-1PFK-1 FBPase-1

ATP

citrate

ADP

AMP

F2.6BP

PFK-1

Regulation of gluconeogenesis

Pyruvate carboxylase

FBPase-1

Pyruvate carboxylase

• Pyruvate carboxylase is being positively regulated by acetyl-CoA.

• The accumulation of acetyl-CoA signals that cell’s energy demands are met.

• Acetyl-CoA also indirectly inhibit pyruvate dehydrogenase complex.