12.Deoxyribonucleotides

12.Deoxyribonucleotides - 12. Deoxyribonucleotide...

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12. Deoxyribonucleotide biosynthesis and nucleotide catabolism 1
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2 Ribonucleotide reductase reduces ADP, GDP, DNA synthesis also requires thymine, which is made from dUDP. Regeneration of the reduced enzyme requires several steps Two cysteines in the enzyme serve as the reductant. dTTP ADP GDP CDP UDP H2O NADP+ NADPH ribonucleotide reductase SH SH S S OH OH O P -O- P -O- CH2 N OH P -O- P -O-CH2 O N dADP dGDP dCDP dUDP Ribonucleotide reductase is located in the cytosol.
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1av8.pdb R2 dimer regulatory sites R2 R2 O O R1 R1 The enzyme has two types of subunits, R1 and R2. Each of the catalytic sites in ribonucleotide reductase has a binuclear Fe center and a stable tyrosyl radical O CHCH2 C=O NH O O C Fe Fe C O O C O O N N N N C O O tyrosyl radical The catalytic sites are at the R1-R2 interfaces 3
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NDP SH SH S SH dNDP Electron transfer to the Tyr radical generates a Cys radical near the substrate-binding site. OH OH O P -O- P -O-CH2 N H H H OH O P -O- P -O-CH2 N H H H OH 5 P -O- P -O-CH2 N H O O H O O H P -O- P -O-CH2 N S S S S H+ 2 H+ Ribonucleotide reduction occurs through free-radical intermediates OH OH O H P -O- P -O-CH2 N
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Regulation of ribonucleotide reductase at two allosteric sites balances the rates of formation of the different deoxyribonucleotides dTTP inhibits reduction of CDP & UDP, and activates reduction of GDP. ATP activates reduction of CDP & UDP. dATP inhibits and ATP activates the enzyme with all substrates. allosteric effectors substrates activity regulation site substrate- specificity site catalytic site ATP, dATP, dGTP, dTTP ADP, CDP, UDP, GDP ATP, dATP - + SH SH HS HS O R2 R2 R1 R1 6
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At the activity-regulation site, dATP decreases Vmax and ATP increases Vmax for the reactions of all the ribonucleotides R2 catalytic site R1 substrate- specificity site SH SH activity regulation site ADP ATP dADP dATP - + 7
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At the specificity site, ATP, dATP, dTTP and dGTP tune the relative affinities for CDP, UDP, GDP and ADP + - - - - ATP ADP dADP dATP GDP dGDP dGTP UDP dUDP dTTP CDP dCDP dCTP + + + + 8
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Two sets of redox proteins carry electrons from NADPH to ribonucleotide reductase (RNR) H3N-CH-CH2CH2-CO-NH-CH-CO-NH-CH2- CO2 + CO2 - - CH2 SH Glutathione ( γ -Γλυ-Χψσ-Γλψ29 ισ τηε μαιν ρεδοξ βυφφερ ιν τηε χψτοσολ οφ μοστ ευκαρψοτιχ χελλσ thioredoxin
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12.Deoxyribonucleotides - 12. Deoxyribonucleotide...

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