Several reviews and studies have previously described the structural basis for the allosteric regulation and cluster assembly of class I RNRs (Ando et al., 2011 Hofer et al., 2012 Ahmad and Dealwis, 2013 Tomter et al., 2013).Ĭlass I RNRs can be further subdivided into class Ia, Ib, and Ic enzymes (see Table Table1) 1) based on the type of metal center required to generate the protein radical. The active form of RNR in eukaryotes and prokaryotes comprises two proteins (R1 + R2 or α + β) associated in a dimeric or other oligomeric forms, such as α nβ m (where n can be 2, 4 or 6 and m 1, 2, 3 or more). The β subunit harbors the metallocofactor essential for the initiation of nucleotide reduction. The α subunit contains the catalytic subunit, containing the active site where nucleotide reduction occurs, and two allosteric sites, involved in the allosteric regulation of substrate specificity and general enzyme activity. These enzymes comprise two homodimeric subunits, namely R1 (or α) and R2 (or β). Extensive reviews concerning allosteric regulation at the biochemical level have previously been published (Reichard, 1997 Nordlund and Reichard, 2006 Hofer et al., 2012 Ahmad and Dealwis, 2013), thus this review will focus on the bacterial RNR rather than the eukaryotic RNR.Ĭlass I RNRs are the best-known and most-studied enzymes. RNR activity is controlled at two different levels: substrate specificity, in which the binding of different nucleotides results in the reduction of each specific NTP at the active site, and enzymatic activity, in which the binding of ATP, or dATP respectively activates or inhibits enzymatic activity (Figure (Figure2). Thus, one of the most important aspects of the dNTP supply required for DNA synthesis and repair is the tight regulation of RNRs at different levels, including the allosteric regulation of enzyme activity, transcriptional regulation, and cell cycle-specific proteolysis in mammalian cells. Unbalanced dNTP levels could lead to increased mutation rates (Mathews, 2006). Reduction of the four different nucleotides (ATP/CTP/GTP/TTP) occurs at a single active site in each polypeptide chain, therefore the tight regulation of dNTP levels is important for each dividing cell.
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