1. Régulation de la production dun nucléotide triphosphate Uridylate en thymidylate Cycle des Cofacteurs Deux médicaments anti-cancer Structure & Function des protéines chez les animaux 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-phosphates in the body. The purpose of this pathway is the synthesis of DNA. Ribonucleotide reductase controls the production of deoxynucleoside tri-phosphates in the body. 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. rADP rCDP rGDP rUDP The purpose of this pathway is the synthesis of DNA. DNA is synthesized from deoxyribonucleoside triphosphates (dNTPs) by an enzyme, DNA polymerase, which is represented by the unlabeled green rectangle. Here are the four different ribonucleoside diphosphates dADP, dCDP, dGDP, dUDP which are converted, by ribonucleotide reductase, to deoxyribonucleoside diphosphates. DNA is synthesized from deoxyribonucleoside triphosphates (dNTPs) by an enzyme, DNA polymerase, which is represented by the unlabeled green rectangle. Here are the four different ribonucleoside diphosphates which are converted, by ribonucleotide reductase, to deoxyribonucleoside diphosphates. Three of the deoxyribo- nucleoside diphosphates are converted to deoxyribo- nucleoside triphosphates by phosphorylation reactions. dNTP Inhibition allostérique Regulation allostérique Structure & Function des protéines chez les animaux Sujet suivant Sujet précédent Étape suivante Recommencer Faire un essai Aide Son :oui/non Quitter Contenu Here are the four different ribonucleoside diphosphates which are converted, by ribonucleotide reductase, to deoxyribonucleoside diphosphates. Three of the deoxyribo- nucleoside diphosphates are converted to deoxyribo- nucleoside triphosphates by phosphorylation reactions. 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 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-phosphates in the body. The purpose of this pathway is the synthesis of DNA. Ribonucleotide reductase controls the production of deoxynucleoside tri-phosphates in the body. 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. rADP rCDP rGDP rUDP The purpose of this pathway is the synthesis of DNA. DNA is synthesized from deoxyribonucleoside triphosphates (dNTPs) by an enzyme, DNA polymerase, which is represented by the unlabeled green rectangle. Here are the four different ribonucleoside diphosphates dADP, dCDP, dGDP, dUDP which are converted, by ribonucleotide reductase, to deoxyribonucleoside diphosphates. DNA is synthesized from deoxyribonucleoside triphosphates (dNTPs) by an enzyme, DNA polymerase, which is represented by the unlabeled green rectangle. Here are the four different ribonucleoside diphosphates which are converted, by ribonucleotide reductase, to deoxyribonucleoside diphosphates. Three of the deoxyribo- nucleoside diphosphates are converted to deoxyribo- nucleoside triphosphates by phosphorylation reactions. dNTP Inhibition allostérique Regulation allostérique Structure & Function des protéines chez les animaux Sujet suivant Sujet précédent Étape suivante Recommencer Faire un essai Aide Son :oui/non Quitter Contenu Here are the four different ribonucleoside diphosphates which are converted, by ribonucleotide reductase, to deoxyribonucleoside diphosphates. Three of the deoxyribo- nucleoside diphosphates are converted to deoxyribo- nucleoside triphosphates by phosphorylation reactions. 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, dUDPdNTPDNAdNTP 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 thymidylate Structure & Function des protéines chez les animaux 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 Sujet précédent Étape suivante Hit P to go back Faire un essai Aide Son :oui/non Quitter Contenu Index Tutoriale Recommencer

5. rADP rCDP rGDP rUDP ribonucleotide reductase dADP, dCDP, dGDP, dUDPdNTPDNAdNTP allosteric feedback dUMP thymidylate synthase dTMP dTDP 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 cofacteurs Structure & Function des protéines chez les animaux 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 Sujet précédent Étape suivante Faire un essai Aide Son :oui/non Quitter Contenu Index Tutoriale Recommencer

6. Deux médicaments anti-cancer Structure & Function des protéines chez les animaux rADP rCDP rGDP rUDP ribonucleotide reductase dADP, dCDP, dGDP, dUDPdNTPDNAdNTP allosteric feedback dUMP thymidylate synthase dTMP dTDP 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 Sujet précédent Étape suivante Faire un essai Aide Son :oui/non Quitter Contenu Index Tutoriale Recommencer

7. Sommaire Structure & Function des protéines chez les animaux rADP rCDP rGDP rUDP ribonucleotide reductase dADP, dCDP, dGDP, dUDPdNTPDNAdNTP allosteric feedback dUMP thymidylate synthase dTMP dTDP 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 Sujet précédent Étape suivante Faire un essai Aide Son :oui/non Quitter Contenu Index Tutoriale Recommencer

8. Aide 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. Structure & Function des protéines chez les animaux Sujet suivant Sujet précédent Étape suivante Faire un essai Aide Son :oui/non Quitter Contenu Index Tutoriale Recommencer