Ribonucleotide Reductase

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Introduction

Ribonucleotide reductase, RNR, is one of the major enzymes that aids in the synthesis of deoxyribonucleotides. These precursors of DNA are vital for DNA synthesis, so RNRs are required in all living cells to replicate and repair DNA. The reaction catalyzed through RNR is the only biochemical pathway that can synthesize new deoxyribonucleotide triphosphates (dNTPs). This enzyme has led to and contributed to the evolution of genetic material that exists today. RNR consists of three different classes: I, II, and III. The classes differ in which they require different metal cofactors in order to initiate the reaction. This then leads to different environmental factors affecting the enzyme and its different classes.

Function

The conversion from ribonucleotides to deoxyribonucleotides is a radically-based reaction. Organic free radicals are stored by RNR until they are needed for catalysis.

Disease

Activity of RNR is controlled by substrate specificity and enzymatic activity. Substrate activity functions by allowing the binding of different nucleotides which results in the reduction of a specific NTP. This regulation occurs at the active site. ATP or dATP can bind to activate or inhibit activity which allows for enzymatic activity to be controlled. Mutations can occur within the genome if there is an imbalance in the pools of dNTPs. These are the building blocks for DNA, and if the pool is altered, then it can lead to genomic instability.

Relevance

Structure

The structure of ribonucleotide reductase is composed of two components. One portion is the radical generator which produces and stores the radical. This portion is used to oxidize the substrate to its radical form which is the first step of the overall reaction. The second portion of the structure consists of a reductase. The reductase is the same for all three classes, but the radical generator differs. The three different classes of this enzyme have a cysteine residue that is located at the protein loop of the active site. The protein loop is in the center of the alpha, beta-barrel of the structural motif. The cysteine residue is conserved until it is converted to a thiyl radical. The conversion to the thiyl radical is needed to initiate substrate turnover. The different classes of RNR are different but do show some similarities which suggest that they all evolved from one common reductase.