Enzyme Regulation I - Oregon State Universityoregonstate.edu/.../Keynotes/14EnzymeRegulation.pdf ·...
Transcript of Enzyme Regulation I - Oregon State Universityoregonstate.edu/.../Keynotes/14EnzymeRegulation.pdf ·...
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EnzymeRegulationI
Dr.KevinAhern
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EnzymeRegulationMechanisms
1. Allosterism 2. Covalent Modification 3. Control of Synthesis 4. Availability of Substrate
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ControlofEnzymeActivity
Substrate Does Not Change Enzyme Binding of Substrate Substrate Does Change Enzyme
Binding of Substrate
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Homotropic and Heterotropic Effectors
ControlofEnzymeActivity
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Six Regulatory SubunitsSix Catalytic Subunits
Aspartate Transcarbamoylase (ATCase)
ControlofEnzymeActivity
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ControlofEnzymeActivity
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ControlofEnzymeActivity
Aspartate Transcarbamoylase (ATCase)
• Aspartate - Amino Acid • ATP - High Energy, Purine • CTP - End Product of Pathway
Substrates
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ControlofEnzymeActivity
ATCase is Affected by One of its Substrates - Aspartate Aspartate is a Homotropic Effector of ATCase
Binding of Aspartate by ATCase Favors the R-State so Additional Substrate Binding is Favored
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ControlofEnzymeActivity• Allosteric Control of ATCase
No ATP
2 mM ATP
In the Presence of ATP, the V0 is Increased Compared to No ATP
ATP Activates ATCase (Converts to R State)
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ControlofEnzymeActivity• Allosteric Control of ATCase
CTP Reduces the Activity of ATCase - Converts to T State
V0 Decreases as [CTP] Increases
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ControlofEnzymeActivity• Allosteric Control
Six Catalytic Subunits - C1 to C6
Six Regulatory Subunits - R1 to R6
ATP and CTP Bind Regulatory Sites ATP Favors R State CTP Favors T State
Aspartate Binds to Catalytic Subunits
Favors R State
Aspartate is a Substrate, but Neither ATP nor CTP is.
All Affect the Enzyme
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ControlofEnzymeActivity• Allosteric Control
At Low [S], ATCase in T State
As [S] Increases, ATCase Increasingly in R State
At High [S], ATCase Mostly in R State
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ControlofEnzymeActivity• Allosteric Control
Thus, ATCase is Most Active When Energy (ATP) is High and When Pyrimidines are Low in
Concentration Relative to Purines
ATCase is Least Active When PyrimidineConcentration (CTP) is High
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FeedbackInhibition• Aspartate Transcarbamoylase (ATCase)
ATCase
Carbamoyl Phosphate
Carbamoyl Aspartate
Aspartate
Pi
CTP
Multiple Reactions
Accumulating CTP Inhibits Enzyme
Cells in a High Energy State Have Lots of ATP
ATP Activates ATCase
Cells With Abundant Amino Acids Have Lots of
Aspartate - Activates ATCase
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CovalentModification
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CovalentModification
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ZymogenActivation
Trypsinogen
Enteropeptidase
TrypsinCascading Effects
Chymotrypsinogen
Chymotrypsin
Proelastase
Elastase
Procarboxypeptidase
Carboxypeptidase
Prolipase
Lipase
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ControlofEnzymeofActivity• Zymogens
• Protease Precursors • Pepsinogen • Proenteropeptidase • Trypsinogen • Chymotrypsinogen • Procarboxypeptidases • Blood Clotting Proteins • Procaspases • Proelastase
• Other • Pacifastin • Plasminogen • Angiotensinogen • Prolipase • Pre-proinsulin
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ControlofEnzymeofActivity• Other Covalent Modifications to Proteins
• Phosphorylation - Kinase Cascades • Acetylation - Histones • Formylation - All Prokaryotic Proteins • Acylation - Anchored Membrane Proteins (SRC) • ADP Ribosylation - Transcription Factors • Prenylation - Ras • Sulfation - Serine Protease Inhibitors • Ubiquitination - Many Proteins • γ-Carboxylation - Clotting Proteins
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ControlofEnzymeofActivity• γ-Carboxylation
Glutamate Side Chain γ - carboxyglutamate
Carboxyl Group Added
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MetabolicMelody
Protein Wonderland
(to the tune of “Winter Wonderland”) Copyright © Kevin Ahern
Mechan-i-sm . . determines How an en . . zyme is workin’
Here are the ways That each elastase
Breaks a peptide bond so easily
Starting with the binding of the substrate Catalytic triad is the star
Histidine’s electron sink reacts to
Pull a proton from a serine’s a-r-r-r-r
Then the al . . . koxide ion Gets elec . . . trons a-flyin
It makes a big fuss For one nuc-le-us
And breaks and makes a bond with carbonyl
Then the process switches in its action
Water comes to free the carbonyl
Loss of proton yields hydroxide ion
Attacking on the peptide bound there still -ll -ll
Which the en . . . . zyme releases
Otherwise . . . action ceases
The process is done
Until the S1
Binds a substrate starting up again