Metabolic Regulation

- .

- :

- Enzyme activity

- Cell surface receptors

Metabolic RegulationGenetic Level Regulation:

Control which protein is synthesized through adjusting the rate of transcription of that gene:

Feedback repression: The of enzymatic activity accumulates and blocks t .

For repression, the is required which can bind to the operator region and hinder RNA polymerase binding.

The repressor protein can block transcription when bound to the (typically the end product of the pathway).

m-RNARNA polymerase

repressor

Promoter Operator Gene 1 Gene 2 Gene 3

Normal Transcription

RNA polymeraserepressor

Promoter Operator Gene 1 Gene 2 Gene 3

corepressor

Transcription Blocked

DNA template

inactive

active

DNA template

Genetic Organization of the Tryptophan Operon

DNA template

encoding repressor

encoding related enzymes for tryptophan synthesisfrom chorismate.

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.

Metabolic regulation

Genetic Level Regulation:

Induction: a ( 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.

m-RNARNA polymerase

Promoter Operator Gene 1 Gene 2 Gene 3

Transcription Permitted

RNA polymeraserepressor

Promoter Operator Gene 1 Gene 2 Gene 3

Transcription Blocked

repressor

Inducer

DNA template

DNA template

Example

• Inducer: allolactose modified from lactose in the cell.

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.

m-RNARNA polymerase

Promoter Operator Lac z Lac y Lac a

repressor

allolactose

Lac i

Lac i encoding repressor.

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.

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.

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 Regulation - Metabolic Pathway Control:

- The can be controlled by enzyme activity.

- The activity of allosteric enzymes can be controlled by effectors including inhibitors and activators.

- Most often the reaction in the pathway is inhibited by accumulation of : feedback inhibition or end-product inhibition.

What are the differences between feedback repression and

feedback inhibition?

Reduced enzyme activity

Operator on DNA template occupied by the complex

Effect

End product + enzyme

End product +

repressorComplex formed

The respective reaction is inhibited.

Blocked Transcription

Consequence

Cellular:

Activity of enzyme

Genetic: RNA transcription

Regulation level

Feedback inhibition

Feedback repression

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.

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.

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.

Metabolic Regulation

- Concerted feedback inhibitionMore 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 E3 and E4, respectively → M3 will accumulate →the pathway is inactivated if both P1 and P2 are high.

M1 M2 M3M4

M5

P1

P2

X X

XE1 E2 E4

E3

Sequential Feedback Inhibition

Concerted

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.

Cumulative

Inosine 5-mono-phosphate (IMP)

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

Isoenzyme, concerted feedback, sequential and cumulative feedback inhibition