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. Class I ribonucleotide reductase produces the stable radical, tyrosyl, through the dinuclear iron center of the subunit. This class is the most studied and most well known enzyme that is a part of the RNR family. It is composed of two subunits, alpha and beta, that are homodimeric. The alpha subunit contains the active site and two allosteric sites. The active site contains a catalytic subunit, and the allosteric sites are used for regulation, enzyme activity, and substrate specificity. The beta portion contains the metal cofactor that initiates reduction. Class I is subdivided into three more enzymes that are class Ia, Ib, and Ic. Class one is split even further because it is depending on the specific type of metal center that is needed for protein radical. All three classes share the same function for the beta subunit which is synthesizing the radical which is transferred using a radical transfer pathway. Class Ia requires a di-iron center as the nrdAB gene codes for this enzyme. Class Ib uses either a di-manganese center or a di-ferric center. This specific class differs from the other class I enzymes by lacking the active site located at the N-terminal portion of the protein. This enzyme is coded by the gene nrdHIEF Class Ic is encoded by the nrdAB gene, and it requires a manganese-iron center. Class I and its subdivision are all aerobic and require oxygen for the generation of the radical. This enzyme can be found in eukaryotes, archaea, eubacteria, and bacteriophages.

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. Having accurate DNA repair and replication allows for development, tumor-free cells, and growth. Having issues within the genome can cause several human diseases, mitochondrial disorders, and cause a person to be more susceptible to infection and cancer. High expressions of RNR is a main characteristic for cancers since it influences DNA replication so heavily. For this reason, RNRs play a major role in targeting anticancer and antibacterial drugs and therapies. RNR inhibitors are being studied to see if they can potentially serve as cancer treatment that is effective. More and more research is being done everyday in order to fully understand ribonucleotide reductase and all of its classes. For decades, dNTP machinery and RNR has been used and exploited for therapeutic benefits. They serve an important target for developing an efficient cancer drug.

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.