Metabolic Regulation

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Metabolic Regulation

• Genetic level
• Cellular level
• - Enzyme activity

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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. For
repression, the repressor protein is required
which can bind to the operator region and hinder
RNA polymerase binding. The repressor protein
can block transcription only when bound to the
co-repressor (typically the end product of the
pathway).
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Normal Transcription
DNA template
Promoter
Operator
Gene 1
Gene 2
Gene 3
RNA polymerase
m-RNA
repressor
inactive
Transcription Blocked
DNA template
active
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Genetic Organization of the Tryptophan Operon
DNA template
encoding related enzymes for tryptophan synthesis
encoding repressor
Only when the repressor binds with tryptophan, it
can bind on the operator region and block the
transcription.
Operon In prokaryotes, a set of genes, encoding
proteins with related functions, under the
control of a single promoter-operator.
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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.

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Transcription Blocked
Promoter
Operator
Gene 1
Gene 2
Gene 3
RNA polymerase
DNA template
repressor
Transcription Permitted
DNA template
Promoter
Operator
Gene 1
Gene 2
Gene 3
RNA polymerase
m-RNA
repressor
Inducer
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Example

• Inducer allolactose modified from lactose in the
  cell.

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• 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.

Lac i
Promoter
Operator
Lac z
Lac y
Lac a
RNA polymerase
m-RNA
repressor
Lac i encoding repressor.
allolactose
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Catabolite Repression (Glucose Effect)

• 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.

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Metabolic Regulation

• Catabolite Repression (glucose effect)
• When the cell has an energetically favorable
  carbon-energy source (e.g. glucose) 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.

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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)

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Metabolic Regulation

• Cellular Level Regulation - 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.
• Allosteric enzyme enzymes have more than one
  substrate binding site. The binding of one
  substrate to the enzyme facilitates binding of
  other substrate molecules.
• Most often the first reaction in the pathway is
  inhibited by accumulation of the product
  feedback inhibition or end-product inhibition.

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What are the differences between feedback
repression and feedback inhibition?
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Cellular Activity of enzyme
Genetic RNA transcription
Regulation level
End product enzyme
End product repressor
Complex formed
Reduced enzyme activity
Operator on DNA template occupied by the complex
Effect
The respective reaction is inhibited.
Blocked Transcription
Consequence
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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 Please refer to the textbook p.123.
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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.

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The common pathway leading to the synthesis of
the aromatic amino acids contains three isozymes.
Each of these enzymes is specifically
feedback-inhibited by one of the aromatic amino
acids. Note how an excess of all three amino
acids is required to completely shut off the
synthesis of DAHP.
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Metabolic Regulation

• - Concerted feedback inhibition
• More than one end product or all end products
  must be present in excess to repress the first
  enzyme.

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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 E3 and E4, respectively
? M3 will accumulate ?the pathway is inactivated
if both P1 and P2 are high.
E3
E1
E2
E4
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Sequential Feedback Inhibition
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Inosine 5-mono-phosphate (IMP)
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Summary of Metabolic Regulation

• Metabolic regulation
• Genetic level control transcription of genes
  (repression, induction and catabolic repression
  (glucose effect))
• Cellular level
• - Enzyme activity feedback inhibition