5. Wu - Nucleotide Metabolism II

5. Wu - Nucleotide Metabolism II - Conversion of...

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Unformatted text preview: Conversion of nucleotides to deoxyribonucleotides 1 Replaces 2-hydroxyl of ribose by hydrogen: Substrates: NDPs Ultimate reductant: NADPH Ribonucleotide reductase: Rate limiting step in DNA synthesis 2 Activity of ribonucleotide reductase 3 Identical pairs of subunits B1( 2) & B2 ( 2). B1: S substrate specificity site (high anity) A-overall activity site (low anity) Activity control : ATP activates overall activity dATP inhibits overall activity Catalytic site: at the interface between B1 and B2 . cysteine residues : SH groups involved in electron transfer when ribose is reduced to deoxyribose B2 site contains a tyrosine whose OH is crucial to the enzyme activity target of antitumor agent hydroxyurea Ribonucleotide reductase: the enzyme 4 5 Ribonucleotide reductase Requires: thioredoxin thioredoxin reductase (FAD containing protein) NADPH During enzyme catalysis, SH of the cysteine residues oxidized to disulfides -- Disulfide reduction to free sulfhydryls required to restore ribonucleotide reductase activity Reduction of disulfides requires a peptide coenzyme present in ribonucleotide reductase, called thioredoxin 6 Ribonucleotide reductase Oxidation of SH in thioredoxin to disulfides is coupled with restoration of free SH in Cys of ribonucleotide reductase, restoring the enzymatic activity Oxidized thioredoxin reduced by thioredoxin reductase, coupled with oxidation of NADPH Ribonucleotide reductase is regulated allosterically by nucleotides 7 Thioredoxin cycle 8 Activity of ribonucleotide reductase 9 S substrate specificity site (high anity; allosteric control) A-overall activity site (low anity allosteric control) binding ATP activates overall activity binding of dATP inhibits Catalytic site lies at the interface between B1 and B2 . 10 Regulation of ribonucleotide reductase: S site sense the relative abundance of dNTPs Also: dATP major ve effector for all substrates dGTP ve effector for CDP/UDP Substrate +ve-ve effectors ADP dGTP dATP GDP dTTP dATP dGTP UDP ATP dATP dGTP dTTP CDP ATP dATP dGTP dTTP 11 dUTP pyrophosphatase Thymidylate synthesis 12 One-carbon charged THF 13 Thymidylate synthesis/tetrahydrofolate cycle dUDP dUTP; enzyme: dUDPkinase dUTP dUMP; enzyme: dUTP pyrophosphatase...
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5. Wu - Nucleotide Metabolism II - Conversion of...

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