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Metabolic regulation
Metabolic regulation:
- Genetic level
- Cellular level:
- enzyme activity
- Cell surface receptors
Metabolic regulation
Genetic level regulation:
Control which protein is synthesized through adjusting
the rate of transcription of that gene:
- feedback repression: the end product of enzymatic
activity accumulates and blocks transcription.
a repressor protein bound to the end product (corepressor) can bind to the operator region and hinder
RNA polymerase binding.
Normal Transcription
DNA template
Promoter
Operator
Gene 1
Gene 2
Gene 3
m-RNA
RNA polymerase
repressor
inactive
Transcription Blocked
DNA template
Promoter
RNA polymerase
Operator
Gene 1
repressor
corepressor
active
Gene 2
Gene 3
In Procaryotes
Operon: A set of genes, encoding proteins
with related functions, under the control of
a single promoter-operator.
DNA template
Promoter
Operator
Gene 1
Gene 2
Gene 3
m-RNA
RNA polymerase
repressor
DNA template
encoding related enzymes for tryptophan synthesis
encoding repressor
Genetic organization of the Tryptophan operon
Metabolic regulation
Genetic level regulation:
- Induction: a metabolite ( often a substrate for a
pathway) accumulates and acts as an inducer of
transcription.
The inducer will bind the repressor protein, and
the complex is inactive as a repressor.
Transcription Blocked
Promoter
Operator
RNA polymerase
Gene 1
repressor
Gene 2
Gene 3
DNA template
Transcription Permitted
DNA template
Promoter
Operator
Gene 1
Gene 2
Gene 3
m-RNA
RNA polymerase
repressor
Inducer
Catabolite Repression
(Glucose Effect)
e.g. The lactose operon controls the synthesis of
three proteins (Lac z (lactase), lac y, lac a )
involved in lactose utilization as a carbon and
energy source in E. coli.
Promoter
Operator
Lac z
Lac y
Lac a
m-RNA
RNA polymerase
repressor
allolactose
Example
• Inducer: allolactose modified from lactose in the cell.
• Induction of allolactose might not be sufficient for
maximum transcription if a carbon-energy source (e.g.
glucose) preferred to lactose is present.
• Only when glucose is depleted, the cell will expend
energy to create a pathway to utilize the less favorable
carbon-energy source lactose.
Metabolic regulation
Catabolite repression (glucose effect)
When the cell has an energetically favorable
carbon-energy source available,
it will not expend significant energy to create a
pathway for utilization of a less favorable
carbon-energy source;
it will not transcript the related enzyme for such
reaction.
Metabolic regulation
Genetic level regulation:
- Some genes are regulated.
- others are not (constitutive):
their gene products are made at a relatively
constant rate irrespective of changes in growth
conditions.
( enzymes are expected to use under almost any
conditions such as that involved in glycolysis)
Metabolic regulation
Cellular level- metabolic pathway control:
- The metabolic pathway can be controlled by
enzyme activity.
- The activity of allosteric enzymes can be
controlled by effectors including inhibitors and
activators.
- Most often the first reaction in the pathway is
inhibited by accumulation of the product:
feedback inhibition or end-product inhibition.
What are the differences
between feedback repression
and feedback inhibition?
Feedback
repression
Regulation level Genetic: RNA
transcription
Complex formed End product +
repressor
Feedback
inhibition
Cellular:
Activity of
enzyme
End product +
enzyme
Effect
Operator on DNA
template occupied
by the complex
Reduced enzyme
activity
Consequence
Blocked
Transcription
The respective
reaction is
inhibited.
Metabolic regulation
Cellular level- metabolic pathway controls:
The activities of a group of enzymes (pathway) can be
controlled.
-
Isozymes
-
Concerted feedback
-
Sequential feedback
-
Cumulative feedback
Metabolic regulation
Cellular level- metabolic pathway controls through:
- Isozymes
- A number of separate enzymes initially carry out the
same conversion, each of which is sensitive to
inhibition by a different end product.
Metabolic regulation
- Isozymes
Glucose + ATP → glucose-6-phosphate + ADP
Glucokinase and hexokinase I, II, III
Glucokinase is not inhibited by glucose-6-phosphate
while other three enzymes are.
Metabolic regulation
- Concerted feedback inhibition
More than one end product or all end products must be
present in excess to repress the first enzyme.
Metabolic regulation
- Sequential feedback inhibition
the common steps are inhibited by the product before
the branch, and the first enzyme of each branch is
inhibited by the branch product.
High levels of P1 and P2 inhibit enzyme E4 and E5,
respectively → M3 will accumulate →the pathway is
inactivated if both P1 and P2 are high.
P1
M1 X
E1
M2
M3
E2
X
M4
E3
X E4
M5
P2
Sequential feedback inhibition
Metabolic regulation
- Cumulative feedback inhibition or cooperative
feedback inhibition
- A single allosteric enzyme may have effector sites for several end products of a pathway;
- each effector causes only partial inhibition.
- Full inhibition is a cumulative effect.
Concerted
Cumulative
Inosine 5-mono-phosphate (IMP)
Metabolic regulation
Cellular level- how cell senses its extracellular
environment
- Mechanisms to transport small molecules across
cellular membrane:
-Energy-independent uptake:
- passive diffusion
- facilitated diffusion
- Energy-dependent uptake
- Active transport
- Group translocation
Metabolic regulation
Energy-independent uptake:
- passive diffusion: Molecules move down a
concentration gradient from high to low
concentration.
The cytoplasmic membrane consists of lipid core
with very small pores:
- water and oxygen uptake
- charged and large molecules can not cross.
Metabolic regulation
Energy-independent uptake:
- Facilitated transport: Molecules move down a
concentration gradient from high to low
concentration with a carrier molecule (protein).
- The protein is considered embedded in the
membrane.
- The transport can result in the exit and entry of
the targeted molecule.
e.g. Sugar and low-molecular-weight
organics in Eucaryotes. Glycerol in procaryotes.
Metabolic regulation
Energy-dependent uptake:
- Active transport is similar to facilitate transport
but against concentration gradient.
- carrier proteins embedded in the cellular
membrane are necessary components.
- energy is required.
pH (proton motive force) or ion gradients
(hydrolysis of ATP) between inside and outside
cells.
e.g. K+ transport
Metabolic regulation
Energy-dependent uptake:
- Group translocation : chemical modification of the
substrate during the process of transport.
- energy is required:
- the substrate is modified when cross the
membrane and trapped inside the cell irreversibly.
e.g. Phophotransferase system:
Energy source: phosphoenolpyruvate (PEP)
sugar (extracellular) + PEP(intracellular) →
sugar-P(intracellular) + pyruvate (extracellular)
Metabolic regulation
Cell level-role of cell receptors in metabolism and
cellular differentiation
- Almost all cells have receptors (protein) on their surfaces
providing a cell with information about its environment.
- Surface receptor can bind a chemical in the extracellular
space which control the direction of cell movement
responding to the gradient of chemical, light or oxygen.
- Quorum sensing molecule can sense cell concentration
depending on intracellular receptor protein
- Some surface receptor of higher organism can respond
to steroids and growth factors (proteins).
- Some receptors attach cells to surfaces.
Summary of Metabolic Regulation
Metabolic regulation:
• Genetic level: control transcription of genes (repression,
induction and glucose effect)
• Cellular level:
- enzyme activity: feedback inhibition
Isoenzyme, concerted feedback, sequential and
cumulative feedback inhibition
- Cell surface receptors:
- Control the cell movement.
- Sense the cell concentrations.
- Respond to steroids and growth factors (proteins).
- Attach cells to surfaces