Régulation de la production Régulation de la production d’un nucléotide triphosphated’un nucléotide triphosphate

(1)

Régulation de la production Régulation de la production

d’un nucléotide triphosphate d’un nucléotide triphosphate

Uridylate en thymidylate

Cycle des Cofacteurs

Deux médicaments anti-cancer Régulation allostérique

Sommaire

(2)

The thymidine triphosphate (TTP) pathway provides an important example of the

regulation of enzyme activity in the body.

Enzymes are represented as green rectangles.

ribonucleotide reductase

Ribonucleotide reductase controls the production of deoxynucleoside tri-

phosphates in the body.

DNA

Enzymes are represented as

green rectangles. Ribonucleotide reductase controls the production of deoxynucleoside tri-

The purpose of this pathway is the synthesis of DNA.

dNTP

DNA is synthesized from deoxyribonucleoside

triphosphates (dNTPs) by an enzyme, DNA polymerase, which is represented by the unlabeled green rectangle.

rCDP rADP rGDP rUDP

The purpose of this pathway is

the synthesis of DNA. DNA is synthesized from deoxyribonucleoside

Here are the four different ribonucleoside diphosphates

dADP, dCDP, dGDP, dUDP

which are converted, by

ribonucleotide reductase, to deoxyribonucleoside

diphosphates.

Here are the four different ribonucleoside diphosphates which are converted, by

diphosphates.

Three of the deoxyribo-

nucleoside diphosphates are converted to deoxyribo-

nucleoside triphosphates by phosphorylation reactions.

dNTP Inhibition

allostérique

Regulation allostérique

Function des

protéines chez les animaux

Sujet suivant

Sujet précédent Étape suivante

Recommencer

Faire un essai

Aide Son :oui/non

Quitter Contenu

diphosphates.

This 2-enzyme pathway is regulated by negative feedback.

When the dNTP concentration

rises, some of the dNTP bind to

to ribonucleotide reductase molecules and decrease their activity by allosteric

inhibition.

This completes the allosteric regulation

section. Note that ribonucleotide reductase catalyzes the committed step that inexorably leads to the dNTPs and

DNA synthesis. Hence, ribonucleotide reductase is allosterically regulated to

control the flow through the pathway and hence the rate of production of the dNTPs. Click again to move on to the next step, uridylate to thymidylate.

Index Tutoriale

(3)

The thymidine triphosphate (TTP) pathway provides an important example of the

regulation of enzyme activity in the body.

Enzymes are represented as green rectangles.

ribonucleotide reductase

DNA

Enzymes are represented as

green rectangles. Ribonucleotide reductase controls the production of deoxynucleoside tri-

dNTP

rCDP rADP rGDP rUDP

The purpose of this pathway is

the synthesis of DNA. DNA is synthesized from deoxyribonucleoside

Here are the four different ribonucleoside diphosphates

dADP, dCDP, dGDP, dUDP

which are converted, by

diphosphates.

dNTP Inhibition

allostérique

Regulation allostérique

Function des

Sujet suivant

Recommencer

Faire un essai

Aide Son :oui/non

Quitter Contenu

diphosphates.

This 2-enzyme pathway is regulated by negative feedback.

When the dNTP concentration

rises, some of the dNTP bind to

to ribonucleotide reductase molecules and decrease their activity by allosteric

inhibition.

This completes the allosteric regulation

section. Note that ribonucleotide reductase catalyzes the committed step that inexorably leads to the dNTPs and

DNA synthesis. Hence, ribonucleotide reductase is allosterically regulated to

control the the rate of pr flow through the pathwaé

and hence oduction of the

dNTPs. Click again to move on to the next step, uridylate to thymidylate.

Index Tutoriale

(4)

ribonucleotide reductase

rADP rCDP rGDP rUDP

dADP, dCDP, dGDP, dUDP

dNTP DNA dNTP

allosteric feedback

Here is the negative feedback

loop regulating the production

of deoxyribonucleoside tri- phosphates.

Uridylate requires the addition

of a methyl group, to make thymidylate, for DNA

synthesis. The first step is dephosphorylation to

deoxyuridine monophosphate.

dUMP

dTMP

thymidylate synthase

The methyl group is added by thymidylate synthase, which converts dUMP to thymidine monophosphate (dTMP)

dTDP

Uridylate en Uridylate en

thymidylate thymidylate

Function des

Uridylate requires the addition

of a methyl group, to make thymidylate, for DNA

synthesis. The first step is dephosphorylation to

deoxyuridine monophosphate.

The methyl group is added by thymidylate synthase, which converts dUMP to thymidine monophosphate (dTMP).

Two phosphorylation events convert dTMP to thymidine triphosphate, dTTP, ready for DNA synthesis.

The methyl group is added by thymidylate synthase, which converts dUMP to thymidine monophosphate (dTMP).

Two phosphorylation events convert dTMP to thymidine triphosphate, dTTP, ready for DNA synthesis.

DNA synthesis requires all four deoxyribonucleoside tri-

phosphates, so dTTP is essential

for DNA synthesis to proceed.

This completes the uridylate to thymidylate section. Note that thymidylate synthase is

essential

to make dTTP and hence DNA.

Click again to move on to the next

section, cofactor cycling.

Sujet suivant

Hit P to go back

Faire un essai

Aide Son :oui/non

Quitter Contenu

Index Tutoriale Recommencer

(5)

rCDP rADP rGDP rUDP

ribonucleotide

reductase dADP, dCDP, dGDP, dUDP

dNTP

DNA dNTP

allosteric feedback

dUMP

thymidylate synthase thymidylate

synthase dTDP dTMP

The thymidine triphosphate (TTP) pathway provides an important example of the regulation of enzyme

activity in the body. Enzymes are represented as green rectangles.

The most important enzyme for normal regulation of production of deoxynucleoside tri-phosphates in the body is ribonucleotide

reductase.

Thymidylate synthase activity is essential for DNA synthesis.

thymidylate synthase

The most important enzyme for normal regulation of production of deoxynucleoside tri-phosphates in the body is ribonucleotide

reductase.

methylene tetrahydrofolate

Thymidylate synthase activity is essential for DNA synthesis.

Thymidylate synthase adds a

methyl group to dUMP. The methyl group comes from the cofactor, methylene tetrahydrofolate,

dihydrofolate

which is converted to dihydrofolate.

tetra- hydrofolate

Thymidylate synthase activity

is essential for DNA synthesis. Thymidylate synthase adds a

methyl group to dUMP. The methyl group comes from the cofactor, methylene tetrahydrofolate, which is converted to

dihydrofolate.

Dihydrofolate is recycled back to methylene tetrahydrofolate.

dihydrofolate reductase

Cycle des Cycle des cofacteurs cofacteurs

Function des

Dihydrofolate reductase catalyzes the first step in recycling.

This completes the cofactor cycling

section. The cofactor, methylene tetrahydrofolate, donates a

methyl

group to dUMP. The resulting dihydrofolate is recycled. The recycling starts with the reaction catalyzed by dihydrofolate

reductase.

Sujet suivant

Faire un essai

Aide Son :oui/non

Quitter Contenu

(6)

Deux médicaments anti- Deux médicaments anti-

cancer cancer

Function des

rCDP rADP rGDP rUDP

ribonucleotide

reductase dADP, dCDP, dGDP, dUDP

dNTP

DNA dNTP

allosteric feedback

dUMP

thymidylate synthase thymidylate

synthase dTDP dTMP

thymidylate synthase

methylene tetrahydrofolate

dihydrofolate

tetra- hydrofolate

dihydrofolate reductase

Thymidylate synthase and dihydrofolate reductase are the most important targets for anti-cancer therapy, in this pathway.

fluorodeoxy- uridylate

Fluorodeoxyuridylate is a suicide inhibitor of

thymidylate synthase.

Fluorodeoxyuridylate

is formed in the cell from the drug, uracil.

methotrexate

Methotrexate is a competitive inhibitor of dihydrofolate

reductase (DHFR).

Fluorodeoxyuridylate is a suicide inhibitor of

thymidylate synthase.

Fluorodeoxyuridylate

is formed in the cell from the drug, fluorouracil.

Methotrexate is a competitive inhibitor of dihydrofolate

reductase (DHFR).

Either fluorouracil or

methotrexate has the effect of

blocking the conversion of dUMP to dTMP, thus

preventing DNA synthesis.

DNA synthesis is essential for cell proliferation. Thus, fluorouracil and methotrexate, in preventing DNA synthesis, inhibit cell proliferation.

This prevents tumors from growing,

but also interferes with those normal

cells that need to proliferate, producing side-effects.

Sujet suivant

Faire un essai

Aide Son :oui/non

Quitter Contenu

(7)

Sommair Sommair

e e

Function des

rCDP rADP rGDP rUDP

ribonucleotide

reductase dADP, dCDP, dGDP, dUDP

dNTP

DNA dNTP

allosteric feedback

dUMP

thymidylate synthase thymidylate

synthase dTDP dTMP

thymidylate synthase

methylene tetrahydrofolate

dihydrofolate

tetra- hydrofolate

dihydrofolate reductase fluorodeoxy-

uridylate

methotrexate

Which enzyme regulates the rate of production of deoxy- ribonucleoside triphosphates?

How does thymidine phosphate

differ from uridine phosphate?

This is the end of this module.

(Hint: click on the questions at

the left to hear the answer.

Click the “Take a test” button, above, for more questions.)

Sujet suivant

Faire un essai

Aide Son :oui/non

Quitter Contenu

(8)

Aid Aid e e

• Click the right mouse button to make this presentation fit on your screen.

• Click the left mouse button to move through this presentation; click the right mouse

button for more options.

• The screen buttons with white lettering are functional.

• This presentation is a supplement to Lecture 7, “Metabolic Pathways and Feedback

Mechanisms” and assumes you have the basic knowledge of the structure of

nucleotides that is provided in that lecture.

• Click the right mouse button to make this presentation fit on your screen.

• Click the left mouse button to move through this presentation; click the right mouse

button for more options.

• The screen buttons with white lettering are functional.

• This presentation is a supplement to Lecture 7, “Metabolic Pathways and Feedback

Mechanisms” and assumes you have the basic knowledge of the structure of

nucleotides that is provided in that lecture.

Sujet suivant

Faire un essai

Aide Son :oui/non

Quitter Contenu