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Metabolic regulation Metabolic regulation: - Genetic level - Cellular level: - enzyme activity - Cell surface receptors

Metabolic regulation Metabolic regulation: -Genetic level -Cellular level: - enzyme activity - Cell surface receptors

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Page 1: Metabolic regulation Metabolic regulation: -Genetic level -Cellular level: - enzyme activity - Cell surface receptors

Metabolic regulation

Metabolic regulation:

- Genetic level

- Cellular level:

- enzyme activity

- Cell surface receptors

Page 2: 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 (co-repressor) can bind to the operator region and hinder RNA polymerase binding.

Page 3: Metabolic regulation Metabolic regulation: -Genetic level -Cellular level: - enzyme activity - Cell surface receptors

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

Page 4: Metabolic regulation Metabolic regulation: -Genetic level -Cellular level: - enzyme activity - Cell surface receptors

In ProcaryotesOperon: A set of genes, encoding proteins

with related functions, under the control of a single promoter-operator.

m-RNARNA polymerase

Promoter Operator Gene 1 Gene 2 Gene 3

repressor

DNA template

Page 5: Metabolic regulation Metabolic regulation: -Genetic level -Cellular level: - enzyme activity - Cell surface receptors

Genetic organization of the Tryptophan operon

DNA template

encoding repressor

encoding related enzymes for tryptophan synthesis

Page 6: Metabolic regulation Metabolic regulation: -Genetic level -Cellular level: - enzyme activity - Cell surface receptors

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.

Page 7: Metabolic regulation Metabolic regulation: -Genetic level -Cellular level: - enzyme activity - Cell surface receptors

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

Page 8: Metabolic regulation Metabolic regulation: -Genetic level -Cellular level: - enzyme activity - Cell surface receptors

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.

m-RNARNA polymerase

Promoter Operator Lac z Lac y Lac a

repressor

allolactose

Page 9: Metabolic regulation Metabolic regulation: -Genetic level -Cellular level: - enzyme activity - Cell surface receptors

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.

Page 10: Metabolic regulation Metabolic regulation: -Genetic level -Cellular level: - enzyme activity - Cell surface receptors

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.

Page 11: Metabolic regulation Metabolic regulation: -Genetic level -Cellular level: - enzyme activity - Cell surface receptors

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)

Page 12: Metabolic regulation Metabolic regulation: -Genetic level -Cellular level: - enzyme activity - Cell surface receptors

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.

Page 13: Metabolic regulation Metabolic regulation: -Genetic level -Cellular level: - enzyme activity - Cell surface receptors
Page 14: Metabolic regulation Metabolic regulation: -Genetic level -Cellular level: - enzyme activity - Cell surface receptors

What are the differences between feedback repression and

feedback inhibition?

Page 15: Metabolic regulation Metabolic regulation: -Genetic level -Cellular level: - enzyme activity - Cell surface receptors

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

Page 16: Metabolic regulation Metabolic regulation: -Genetic level -Cellular level: - enzyme activity - Cell surface receptors
Page 17: Metabolic regulation Metabolic regulation: -Genetic level -Cellular level: - enzyme activity - Cell surface receptors
Page 18: Metabolic regulation Metabolic regulation: -Genetic level -Cellular level: - enzyme activity - Cell surface receptors
Page 19: Metabolic regulation Metabolic regulation: -Genetic level -Cellular level: - enzyme activity - Cell surface receptors

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

Page 20: Metabolic regulation Metabolic regulation: -Genetic level -Cellular level: - enzyme activity - Cell surface receptors

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.

Page 21: Metabolic regulation Metabolic regulation: -Genetic level -Cellular level: - enzyme activity - Cell surface receptors

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.

Page 22: Metabolic regulation Metabolic regulation: -Genetic level -Cellular level: - enzyme activity - Cell surface receptors

Metabolic regulation

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

Page 23: Metabolic regulation Metabolic regulation: -Genetic level -Cellular level: - enzyme activity - Cell surface receptors
Page 24: Metabolic regulation Metabolic regulation: -Genetic level -Cellular level: - enzyme activity - Cell surface receptors

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.

M1 M2 M3M4

M5

P1

P2

X X

XE1 E2 E4

E3

Page 25: Metabolic regulation Metabolic regulation: -Genetic level -Cellular level: - enzyme activity - Cell surface receptors

Sequential feedback inhibition

Page 26: Metabolic regulation Metabolic regulation: -Genetic level -Cellular level: - enzyme activity - Cell surface receptors

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

Page 27: Metabolic regulation Metabolic regulation: -Genetic level -Cellular level: - enzyme activity - Cell surface receptors

Inosine 5-mono-phosphate (IMP)

Page 28: Metabolic regulation Metabolic regulation: -Genetic level -Cellular level: - enzyme activity - Cell surface receptors

Metabolic regulationCellular 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

Page 29: Metabolic regulation Metabolic regulation: -Genetic level -Cellular level: - enzyme activity - Cell surface receptors

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.

Page 30: Metabolic regulation Metabolic regulation: -Genetic level -Cellular level: - enzyme activity - Cell surface receptors

Metabolic regulationEnergy-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.

Page 31: Metabolic regulation Metabolic regulation: -Genetic level -Cellular level: - enzyme activity - Cell surface receptors

Metabolic regulationEnergy-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

Page 32: Metabolic regulation Metabolic regulation: -Genetic level -Cellular level: - enzyme activity - Cell surface receptors

Metabolic regulationEnergy-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)

Page 33: Metabolic regulation Metabolic regulation: -Genetic level -Cellular level: - enzyme activity - Cell surface receptors

Metabolic regulationCell 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.

Page 34: Metabolic regulation Metabolic regulation: -Genetic level -Cellular level: - enzyme activity - Cell surface receptors

Summary of Metabolic RegulationMetabolic 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