Regulation of Glucose Metabolism by Intracellular Compounds Pyruvate Glucose-6-phosphate dehydrogenase Phosphoenolpyruvate Pyruvate kinase Pyruvate carboxylase Oxaloacetate Pyruvate Phosphoenolpyruvate carboxykinase Glucose Glycogen NADPH + ribose-5-P or fructose-6-P Glycogen Phosphorylase Glycogen synthase ATP ATP ADP Glucose-6-phosphate Fructose-6-phosphate PGM PGI ATP ATP ADP Phosphofructokinase Fructose bisphosphatase Fructose-1,6-bisphosphate ADP ATP ATP Oxaloacetate GTP GTP + CO 2 GDP Glucose 1-phosphate UDP-Glucose UDP-glucose pyrophosphorylase Hexokinase (–) AMP (+) Low [glycogen] (+) Glucose-6-P (+) AMP (–) ATP (–) Glucose-6-P (–) ATP (–) Citrate (–) Phosphoenolpyruvate (+) AMP (+) Fructose-1,6-bisP (–) NADPH (+) NADP (–) AMP (–) Fructose-2,6-bisP (+) Acetyl-CoA (Malate) (+) Fructose-2,6-bisP (+) AMP (–) ATP FBPase-2 PFK-2 Fructose-6-phosphate Fructose-2,6-bisphosphate (+) Gluconeogenesis (+) Glycolysis FBPase-2 PFK-2 Fructose-6-phosphate Fructose-2,6-bisphosphate (–) Glucose-6-P ATP bound to allosteric site AMP bound to allosteric site
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Regulation of Glucose Metabolism by Intracellular Compoundsbrandt/Chem330/Metabolic_regulation... · Regulation of Glucose Metabolism by Intracellular Compounds Pyruvate Glucose-6-phosphate
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Regulation of Glucose Metabolism by Intracellular Compounds
Pyruvate
Glucose-6-phosphatedehydrogenase
Phosphoenolpyruvate
Pyruvatekinase
Pyruvatecarboxylase
Oxaloacetate
Pyruvate
Phosphoenolpyruvate carboxykinase
Glucose
Glycogen
NADPH+
ribose-5-Por
fructose-6-P
GlycogenPhosphorylase
Glycogensynthase
ATPATP
ADP
Glucose-6-phosphate
Fructose-6-phosphate
PGM
PGI
ATPATP
ADP
PhosphofructokinaseFructosebisphosphatase
Fructose-1,6-bisphosphate
ADP
ATPATP
Oxaloacetate
GTPGTP+ CO2
GDP
Glucose1-phosphate
UDP-Glucose
UDP-glucosepyrophosphorylase
Hexokinase
(–) AMP(+) Low [glycogen](+) Glucose-6-P
(+) AMP
(–) ATP
(–) Glucose-6-P
(–) ATP(–) Citrate(–) Phosphoenolpyruvate(+) AMP
(+) Fructose-1,6-bisP
(–) NADPH(+) NADP
(–) AMP(–) Fructose-2,6-bisP
(+) Acetyl-CoA
(Malate)
(+) Fructose-2,6-bisP
(+) AMP(–) ATP
FBPase-2 PFK-2
Fructose-6-phosphate
Fructose-2,6-bisphosphate
(+) Gluconeogenesis (+) Glycolysis
FBPase-2 PFK-2
Fructose-6-phosphate
Fructose-2,6-bisphosphate
(–) Glucose-6-P
ATPbound to
allosteric site
AMPbound to
allosteric site
Fructose-2,6-bisphosphate synthesis and breakdown
Stereoview of Phosphofructokinase-2/Fructose-bis-phosphatase-2 (Rattus norvegicus, PDB ID 1BIF)
!-D-Fructose-6-phosphate
O
OH
CH2O
OH
H2C
OH
OHP
O
O
O
!-D-Fructose-2,6-bisphosphate
O
OH
CH2O
OH
H2C
OH
OP
O
O
O P
O
O
O
ATP ADP
Phosphofructokinase-2
!-D-Fructose-6-phosphate
O
OH
CH2O
OH
H2C
OH
OHP
O
O
O
!-D-Fructose-2,6-bisphosphate
O
OH
CH2O
OH
H2C
OH
OP
O
O
O P
O
O
O
Pi
Fructosebisphosphatase-2
TCA Cycle Regulatory Enzymes Enzyme
Stimulators
Inhibitors
Comments
Pyruvate carboxylase
Acetyl-CoA
ADP
Several hormones alter the amount of this enzyme: Insulin ↓ Cortisol ↑ Glucagon ↑
Pyruvate dehydrogenase
CoA-SH, NAD, Ca2+, Mg2+, pyruvate, insulin
Acetyl-CoA, NADH, phosphorylation, and ATP
Effect of Mg2+: ATP binds Mg2+ with higher affinity than ADP; high free [Mg2+] means low [ATP]. Mg2+ and Ca2+ activate the phosphatase
Citrate synthase
NAD, CoA-SH, ADP High [oxaloacetate] and [acetyl-CoA]
Citrate, Long chain acyl-CoA, ATP, NADH, succinyl-CoA
Isocitrate dehydrogenase
Ca2+, ADP
ATP, NADH
Isocitrate dehydrogenase is the most important regulatory enzyme in the TCA cycle
α-Ketoglutarate dehydrogenase
Ca2+
NADH, succinyl-CoA
TCA Substrates
O
C
C
CH2
O
O
Oxaloacetate
C O
O
O
C
C
CH3
O
O
Pyruvate
PyruvateCarboxylase
ATP ADP
Pi++
CO2
O
C
C
CH2
O
O
Oxaloacetate
Aspartateaminotransferase
!-ketoglutarate Glutamate
CH2
CH
C O
O
H3N
Aspartate
C CO
O
O
O
CH2 C O
O
CH2C O
C O
O
CH2 C O
O
CH2CH
C O
O
H3N
Glutamate !-ketoglutarate
NAD
NH4
Glutamatedehydrogenase
NADH
O
O
OHOH
CH2O
N
N N
N
NH2
P
O
O
Adenosine Monophosphate(AMP)
AMPdeaminase
NH4O
O
OHOH
CH2O
HN
N N
N
O
P
O
O
Inosine Monophosphate(IMP)
Adenylosuccinatesynthetase
CH2 C O
O
CH
NH3
C
O
O
Aspartate
GTP GDP
Adenylosuccinatemonophosphate
CH2 C O
O
CH
HN
C
O
O
OH
O
OHOH
CH2O
N
N N
N
P
O
HO
Adenylosuccinatelyase
AMP
CH C O
O
CHC
O
O
Fumarate
Glucose Homeostasis Control Hormones
Hormone Receptor Second messenger Mechanism Target tissues
Insulin (51 amino acid heterodimeric peptide)
Tyrosine kinase
Phosphorylated proteins
decreased cAMP
∆ Enzyme activity
Gene transcription
Liver, muscle, adipose, pancreas, many others
Glucagon (29 amino acid peptide)
G-protein coupled cAMP
∆ Enzyme activity
Sometimes gene transcription
Liver, pancreas
Cortisol (steroid) Transcription factor
Altered level of specific mRNA Gene transcription Nearly all