Quiz #4/5. #4: Glycolysis (Tuesday, Feb 20 th ) #5: TCA cycle (Monday, Mar 5 th ) Pathways are in...
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Transcript of Quiz #4/5. #4: Glycolysis (Tuesday, Feb 20 th ) #5: TCA cycle (Monday, Mar 5 th ) Pathways are in...
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Quiz #4/5
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Quiz #4/5• #4: Glycolysis (Tuesday, Feb 20th)
• #5: TCA cycle (Monday, Mar 5th)
• Pathways are in the books
• Quiz will have the entire pathway:–All cofactors will be present–Random intermediate and enzymes removed
• You fill in the missing names
–Draw the structure for 1 intermediate• Indicated by a larger box
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Enzyme Regulation
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Conditions Affecting Enzyme Activity
pHtemperature
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pH
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Effects of pH on Enzyme Activity
• Protonation state of side chains
– Variation in protein structure
– Substrate binding
– catalysis
• Ionization of substrate
– Substrate binding
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Temperature
RelativeActivity
ba
Temperature
Protein unfolding
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Control of Enzyme Availability
Principles of Genetic Regulation
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Types of Enzymes“Control of Gene Expression”
• Constitutive Enzymes: e.g. glycolytic enzymes and gluconeogenic enzymes
• Inducible Enzymes: e.g. -galactosidase
• Repressible Enzymes: e.g. ten enzymes of histidine biosynthesis
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Negative Regulators[Bind to operators or upstream repression
sequences (URS)]
O
O
–I nducer
I nducible
e.g. lactose operonRegulator
(Repressor)Complex
–Corepressor
Regulator(Aporepressor)
Complex(Repressor)
Repressible
e.g. trp operon
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Positive Regulators[Bind to promoters, enhancers or upstream
activation sequences (UAS)]
O
O +I nducer
I nducible
e.g. cAMPRegulator Complex
"Activator"
+Corepressor
Regulator"Activator"
Complex
Repressible
e.g. nit-2
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Regulation of Enzyme Catalytic Activity
Covalent ModificationAllosteric Enzymes
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Principles Governing Controls of Enzyme Catalytic
Activity
• Regulatory Enzymes
– Enzyme catalyzing committed, rate-limiting step (often first step)
– Thermodynamically highly favorable reaction
• Outcomes of Regulation
– Feedback inhibition (fbi) of biosynthetic pathways
– Modulation of metabolic flux
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Reversible Covalent Modification
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Page 390
Protein Modification(Phosphorylation/Dephosphorylation)
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Non-covalent Modification
Effectors or Ligands
Positive: activatorsNegative: inhibitors
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Allosteric Enzymes(Modulation of Enzyme Catalytic
Activity)
• Substrate Binding
• Catalytic Rate
• Both
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Allosteric (Regulatory) Enzymes
R (Active)(I nactive)
SubstratesActivators
I nhibitor
T
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Homotropic Effects
VO
[S]
posit ive cooperativity
negative cooperativity
M—M (Simple Enzyme)
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Heterotropic Effects
positive ef fector
negative ef fector
no ef fectorVo
[S]
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Figure 12-16
Glycogen Phosphorylase
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Regulation of Biosynthetic Pathways
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Rationale for Regulation
CentralMetabolite
Product(e.g. Amino Acid)
Biosynthesis
Catabolism
Macromolecules
Nutrient
Efficiency and Flexibility
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Biological Efficiency
• Biosynthesis– Synthesize precursors not available in diet– Cease synthesis when precursors become
available in diet (pre-existing enzymes)– Produce precursors and macromolecules at
appropriate rates
• Catabolism– Degrade most appropriate nutrients at
appropriate rates
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Biological Flexibility
• Adaptaton to Dietary Changes– Need for biosynthetic products– Catabolism of new nutrients– Control of pre-existing enzymes
• Metabolic Flux– Rates of metabolism reflecting needs
for energy and macromolecular synthesis
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Competing Reactions: Regulation
A
B C
Enzyme 1 Enzyme 2
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Control Mechanisms
• Control of Enzyme Availability
– Induction/repression
• Control of Enzyme Activity
– Covalent/Non-covalent
• Control of Substrate Availability
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Types of Regulation
• Specific: pathway’s substrate or product
• General: needs for C or N sources or growth rates (e.g. energy charge)
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Signals Mediating Regulation
Availability ofSubstrates or Products
(Ligands)
Regulatory Proteins
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Biosynthetic Pathways
CentralMetabolite
Product(Amino Acid)
ATP ADP + Pi
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Simple Feedback Inhibition
X
ATP
CentralMetabolite
Product(Amino Acid)
ADP + Pi
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Complex Feedback Inhibition
CentralMetabolite
Product 1
Product 2
XX
X
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Mechanisms of Complex Feedback Inhibition
• Cumulative: sum of individual inhibitions
• Concerted: both end products required for inhibition
• Isoenzyme: two enzymes, each inhibitable by different end product
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Cumulative Feedback Inhibition
A
GF
EDCBA
GF
EDCB
A
GF
EDCB
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Concerted Feedback Inhibition
A
GF
EDCBA
GF
EDCB
A
GF
EDCB
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Isozymes
A
GF
EDCBA
GF
EDCB
A
GF
EDCB
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Modulation of Metabolic Flux
Energy Charge
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Energy Charge(Daniel Atkinson)
Steady-State E.C. = 0.93
ATP, ADP and AMP = Regulatory Ligands
Energy Charge 12
2ATP + ADP ATP + ADP + AMP
=
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Energy Charge
Anabolic pathways
(Biosynthesis)
• Require ATP
• Activated– High EC (ATP)
• Inhibited– Low EC (AMP)
Catabolic Pathways
(Degradation)
• Produce ATP
• Activated– Low EC (AMP)
• Inhibited– Hig EC (ATP)