Upload
truly
View
49
Download
6
Tags:
Embed Size (px)
DESCRIPTION
Coordinated regulation of glycolysis/gluconeogenesis. High blood glucose. Insulin secretion. 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. p.903. p.887. - PowerPoint PPT Presentation
Citation preview
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
p.903
p.887
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
p.903
Glc
GlcGlc
Glc Glc
p.396
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
Phosphorylase kinase
Glycogen phosphorylase
Glycogen phosphorylase
Glycogen synthesis Glycogen degradation
Activation of protein kinase B (PKB)
Insulin receptor
Insulin
p.587
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
p.587
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
p.578
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
p.436
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
Phosphorylase kinase
Phosphorylase kinase
Glycogen phosphorylase
Glycogen phosphorylase
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.