Download LECT 11 CHOsyn

Application of Carbohydrate
Metabolism
Review of Allosteric sites
Futile Cycling
Insulin and Glucagon
Amino Sugars
Glucose
Glucose
Glucose
J=0
J=0
VF > VR
Rate-controlling
Step
Rate-controlling
Step
Rate-controlling
Step
Lactate
Lactate
Lactate
Glucose
VF < VR
Rate-controlling
Step
Lactate
Adenylate kinase
Rule: the balance of ATP, ADP, and AMP in a cell is
controlled by adenylate kinase. Reactions that elevate
ADP elevate AMP, a major allosteric regulator.
Equation
[ATP][AMP]
2ADP
Biological Reality
10
ADP
ATP + AMP
K=
[ADP]2
100
ATP
2
AMP
Rule: A small change in ATP will have a strongly magnifying
effect on ADP or AMP concentrations in the cell
[ATP][AMP]
Examples in Working Muscle
10
100
ADP
ATP
0.1 mM
1 mM
K=
2
[ADP]2
AMP
0.02 mM
If ATP concentration drops by 10%, adenylate kinase will
readjust the levels of ADP and AMP to compensate
100%
ADP
0.2 mM
-10%
>400%
ATP
AMP
0.9 mM
~0.1 mM
Key ALLOSTERIC Regulatory Points
GLYCOLYSIS-GLUCONEOGENESIS
Glucose
HK
F6P
G6Ptase
PFK-1
G6P G6P
-ATP
-Citrate
+AMP
+F2,6P
PEP
PK
PYR
-Alanine
+F1,6BP
-ATP
PYR
PC
OAA
F6BPtase
FBP
-AMP
-F2,6P
OAA
PEPCK
F6P
PFK-2
FBPase-2
PEP
+Acetyl-CoA +Glucagon,
cAMP
No Allostery
F2,6P
-F6P
-Citrate
+AMP
Fructose-2,6-Bisphosphate
•
•
•
•
•
•
A Major Allosteric Regulator
Synthesized by Phosphofructokinase-2
Destroyed by Fructose-2,6-Bisphosphatase
Powerful Activator of Glycolysis
Powerful Inhibitor of Gluconeogenesis
Not an Intermediate in any Pathway
O3POCH2
Fructose-6-P
OH
O
Fructose-1,6BP
CH2OH
PO3=
6
O3POCH2
-D-Fructose-2,6BP
O
2
OH
PO3=
CH2OH
1
Fructose 2,6 Bisphosphate
STIMULATES GLYCOLYSIS
INHIBITS
GLUCONEOGENESIS
Fructose-2,6-bisPO4 (F2,6BP)
the most important allosteric effector that
regulates glycolysis-gluconeogenesis
Activates PFK-1
Inhibits F1,6-bisPtase
F2,6BP level controlled by rates of synthesis and degradation
F6P
F6P
(-)Citrate
(+)AMP
(+)F6P
F2,6BP
PFK-2
FBPtase-2
Both in Same Protein
F2,6BP
PFK-2
Glycolysis
(-)F6P
FBP-2 (+)Glycerol-3-PO4
Gluconeogenesis
Hormonal Control of F2,6BP
ATP cAPK
Kinase
Phosphatase
Glucagon
Epinephrine
cAMP
Liver
ADP
PFK2 (a)
P
PFK2 (b)
FBPase2 (b)
P
FBPase2 (a)
ATP
cAPK
See P. 458
Inhibits glycolysis
Stimulates
gluconeogenesis
ADP
Glucagon
cAMP
Epinephrine
IN LIVER: cAMP activates the phosphatase that destroys F2,6BP
and inhibits the kinase that makes F2,6BP. The combined effect is
to stimulate gluconeogenesis in liver.
FUTILE CYCLING
F6P
PO4
ATP
H20
ADP
F1,6BP
At steady-state, net reaction is:
ATP + H2O
ADP + PO4
TAKE HOME: To prevent futile cycling, rates of
synthesis and degradation in an ATP-dependent step
must not be the same.
See Page 686 in Textbook
INSULIN VS GLUCAGON
Insulin: Stimulates Glycolysis, Glycogen Synthesis
Insulin is designed to remove blood glucose and
allow cells to metabolized the glucose or make glycogen
Insulin inhibits gluconeogenesis
Glucagon: Promotes Gluconeogenesis, Glycogen Breakdown
Glucagon is designed to raise blood glucose and
assist liver in controlling blood glucose levels
Elevates cAMP in liver and stimulates protein
phosphorylation
Glycogen Synthase
Targets: PEPCK
PK
FBPtase-2
Glycogen Phosphorylase
Amino Sugars
•
•
•
•
Synthesized from D-fructose
Amine group donated by glutamine
Acetylated
Found in GAGS, proteoglycans and
glycoproteins
• Examples are N-acetylglucosamine, Nacetylgalactosamine, N-acetylneuraminic
acid (Sialic acid)
AMINO SUGARS
2nd C
CH2OH
COOH3N-C-H
C=O
HO-C
CH2
+
C-OH
CH2
C-OH
C-NH2
O
CH2OP
F-6-P
CHO
H- C-NH3
HO-C
D-Glucosamine
C-OH
C-OH
CH2OP
L-Glutamine
CHO
Amidotransferase
H- C-N -C-CH3
Acetyl-CoA HO-C O
C-OH
N-Acetyl-D-glucosamine
C-OH
CH2OP
3-Stages of Glycoprotein Synthesis
Assembly of oligosaccharide
chains on Dolichol
Assembly of polypeptide
chain with Asn-X-Ser/Thr
on ribosomes
Final tailoring of
oligosaccharide
chains in Golgi
Finished product for secretion
or intracellular targeting
Energy in Glucose (Aerobic)
Glucose
F1,6BP
F1,6BP:
2 Pyr:
2 NADH
-2 ATP
4 ATP
6 ATP
Mitochondria
2Pyr
2Acetyl-CoA: 2NADH =
2Acetyl-CoA
4CO2
6 ATP
24 ATP
38 ATP
C6H12O6 + 6O2
6CO2 + 6H2O
Go’= -2,850 kJ/mol
Conserved = 38 ATP x 30.5 kJ/ATP = 1,159 kJ
Efficiency = 40.7%
Energy in Succinate
Succinate
Fumarate:
1 FADH2 = 2 ATP
Fumarate
Malate:
0
Malate
OAA:
1 NADH = 3 ATP
OAA
4CO2:
2 cycles = 24 ATP
Total
= 29 ATP
Succinate
COOH
CH2
CH2
COOH
C4H6O4 +
3½ O2
4CO2 + 3H2O
Glucose
CHO
H-C-OH
HO-C-H
H-C-OH
H-C-OH
CH2O
H
C6H12O6 + 6O2
6CO2 + 6H2O