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Chapter 5 (part 4)
Enzyme Regulation
Regulation of Enzyme Activity
Enzyme quantity – regulation of gene expression (Response time = minutes to hours)
a) Transcription
b) Translation
c) Enzyme turnover
Enzyme activity (rapid response time = fraction of seconds)
a) Allosteric regulation
b) Covalent modification
c) Association-disassociation’
d) Proteolytic cleavage of proenzyme
Allosteric Regulation• End products are often inhibitors
• Allosteric modulators bind to site other than the active site
• Allosteric enzymes usually have 4o structure
• Vo vs [S] plots give sigmoidal curve for at least one substrate
• Can remove allosteric site without effecting enzymatic action
Regulation of Enzyme Activity
(biochemical regulation) • 1st committed step of a biosynthetic pathway or
enzymes at pathway branch points often regulated by feedback inhibition.
• Efficient use of biosynthetic precursors and energy
B A C1 3”
3’2
E F G4’ 5’
H I J4” 5”
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Phosphofructokinase( PFK)Fructose-6-P + ATP -----> Fructose-1,6-bisphosphateFructose-1,6-bisphosphate + ADPADP
•PFK catalyzes 1st committed step in glycolysis (10 steps total)
(Glucose + 2ADP + 2 NAD+ + 2Pi 2pyruvate + 2ATP + 2NADH)
•Phosphoenolpyruvate is an allosteric inhibitor of PFK
•ADP is an allosteric activator of PFK
Allosteric modulators bind to site other than the active site and
allosteric enzymes have 4o structure
Fructose-6-P + ATP -----> Fructose-1,6-bisphosphateFructose-1,6-bisphosphate + ADPADP
ADPADP
Allosteric Activator (ADP) binds distal to active site
Vo vs [S] plots give sigmoidal curve for at least
one substrate
Binding of this allosteric inhibitor or this activator does not effect Vmax, but does alter Km
Allosteric enzyme do not follow M-M kinetics
Allosteric T to R transition
Concerted model
Sequential model
ET-I ET ER ER-SI
I S
S
Covalent modification
•Regulation by covalent modification is slower than allosteric regulation
•Reversible
•Require one enzyme for activation and one enzyme for inactivation
•Covalent modification freezes enzyme T or R conformation
Phosphorylation /dephosphorylation
•most common covalent modification
• involve protein kinases/phosphatase
•PDK inactivated by phosphorylation
•Amino acids with –OH groups are targets for phosphorylation
•Phosphates are bulky (-) charged groups which effect conformation
Enzyme Regulation by Association/Disassociation
•Acetyl-CoA Carboxylase
•acetyl-CoA + CO2 + ATP malonyl-CoA + ADP + Pi
•1St committed step in fatty acid biosynthesis
•In presence of citrate activated
•In presence of fatty acyl-CoA inactivated
polymerizedunpolymerized
citrate
Fatty acyl-CoA
Proteolytic cleavage of proenzyme(zymogen)
Proinsulin to Insulin
Blood Clotting
•Clotting involves series of zymogen activations
•Seven clotting factors are serine proteases involved in clotting cascade rxns
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