Lect23 - Lecture 23 Nucleotide Biosynthesis (II) 0...

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0 Lecture 23 Nucleotide Biosynthesis (II)
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1 Important concepts 1. Understand the synthesis of deoxyribonucleotide Understand the mechanisms of ribonucleotide reductase (the roles of R1 and R2 dimers) Understand synthesis of thymidylate 2. Understand the regulation of nucleotide synthesis Understand the regulation of pyrimidine synthesis (CTP inhibition and ATP simulation) Understand the feedback regulation of purine synthesis (IMP, AMP, GMP, and reciprocal substrate of ATP and GTP) Understand the regulation of deoxyribonucleotide synthesis 3. Understand the degradation of nucleotides Regulation of deoxyribonucleotide synthesis
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2 Synthesis of DNA A,G,C, U A,G,C, T Ribonucleoside diphosphate deoxyribonucleoside diphosphate Ribonucleotide reductase 1’ 2’ 3’ 4’ 5’
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3 Synthesis of DNA
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4 Ribonucleotide Reductase in E. coli Accept an e - from a Cys in the active site 3 conserved Cystein
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5 Ribonucleotide Reductase in E. coli • A stable tyrosyl radical contains an unpaired electron delocalized onto its aromatic ring •Generated by a nearby iron center: •Two ferric Fe 3+ •One oxide ion O 2-
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6 Ribonucleotide Reductase in E. coli •One Cys transfers an e - to the tyrosyl radical in R2 •Form a highly reactive cysteine thiyl radical Cys Cys Cys Glu
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7 Ribonucleotide Reductase in E. coli •cysteine thiyl radical attracts a proton from C-3’ of the ribose •Forms a radical at C-3’
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8 Ribonucleotide Reductase in E. coli •The C-3’ radical promotes release of OH - from C-2’ • OH - + proton from 2 nd Cys => H 2 O •Glu protonated
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9 Ribonucleotide Reductase in E. coli •3 rd Cys transfers a hydride ion (one proton and two e - ) to complete reduction at C-2’ •Form a disulfide bond •Glu deprotonated to re-form a C-3’ radical
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10 Ribonucleotide Reductase in E. coli •C-3’ radical recaptures the proton from 1 st Cys •The deoxyribonucleotide is free to leave the enzyme
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11 Ribonucleotide Reductase in E. coli •An e - from R2 reduces the thiyl radical •Disulfide bond is reduced by such as thioredoxin
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Reduction of Ribonucleotide Reductase
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Lect23 - Lecture 23 Nucleotide Biosynthesis (II) 0...

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