Ribonucleotide reductase iron ligands

Metalloenzymes with non-heme di-iron centers in which the two irons are bridged by an oxide (or a hydroxide) and carboxylate ligands (glutamate or aspartate) constitute an important class of enzymes. Two of these enzymes, methane monooxygenase (MMO) and ribonucleotide reductase (RNR) have very similar di-iron active sites, located in the subunits MMOH and R2 respectively. Despite their structural similarity, these metal centers catalyze very different chemical reactions. We have studied the enzymatic mechanisms of these enzymes to understand what determines their catalytic activity [24, 25, 39-41]. 

The emphasis on the study of hemoproteins and the iron-sulfur proteins often distracts attention from other iron proteins where the iron is bound directly by the protein. A number of these proteins involve dimeric iron centres in which there is a bridging oxo group. These are found in hemerythrin (Section 62.1.12.3.7), the ribonucleotide reductases, uteroferrin and purple acid phosphatase. Another feature is the existence of a number of proteins in which the iron is bound by tyrosine ligands, such as the catechol dioxygenases (Section 62.1.12.10.1), uteroferrin and purple acid phosphatase, while a tyrosine radical is involved in ribonucleotide reductase. The catecholate siderophores also involve phenolic ligands (Section 62.1.11). Other relevant examples are transferrin and ferritin (Section 62.1.11). These iron proteins also often involve carboxylate and phosphate ligands. These proteins will be discussed in this section except for those relevant to other sections, as noted above. 

Studies on three different iron—sulfur enzyme systems which all require S-adenosylmethionine (SAM) — lysine 2,3-aminomutase, pyruvate-formate lyase, and anaerobic ribonucleotide reductase — have led to the identification of SAM as a major source of free radicals in living cells (for a recent review, see Atta et ak, 2010). As in the dehydratases, these systems have a [4Fe—4S] centre chelated by only three cysteines with one accessible coordination site. The cluster is active only in the reduced state [4Fe—4S] and appears to combine the two roles described previously, serving both as a ligand for substrate binding and as a redox catalyst (Figure 13.19). Their mechanism again requires that the exposed iron atom of the cluster shifts towards octahedral geometry as it binds... 

Type A PCET reactions describe amino acid radical generation steps in many enzymes, since the electron and proton transfer from the same site as a hydrogen atom [188]. Similarly, substrate activation at C-H bonds typically occurs via a Type A configuration at oxidized cofactors such as those in lipoxygenase [47, 48] galactose oxidase [189-191] and ribonucleotide reductase (Y oxidation at the di-iron cofactor, vide infra) [192]. Here, the HATs are more akin to the transition metal mediated reactions of Section 17.3.1 since the final site of the electron and proton are on site differentiated at Ae (redox cofactor) and Ap (a ligand). 

Lammers M, Follmann H (1983) The Ribonucleotide Reductases A unique Group of Metallo-enzymes Essential for Cell Proliferation. 54 27-91 Le Brun NE, Thomson AJ, Moore GR (1997) Metal Centres of Bacterioferritins or Non-Heam-Iron-Containing Cytochromes bs57. 88 103-138 Leciejewicz J, Alcock NW, Kemp TJ (1995) Carboxylato Complexes of the Uranyl Ion Effects of Ligand Size and Coordinate. Geometry Upon Molecular and Crystal Structure. 82 43-84... 

A number of other metalloenzymes have M 2(His)2(02CR)4 active sites (see Chapter 8.13). Most prominent of these are the di-iron enzymes, including the hydroxylase component of methane monooxygenase (MMOH, Figure 15a) and class 1 ribonucleotide reductase R2 proteins (Figure ISb). " These enzymes have two conserved Asp/Glu(Xaa)nGluXaaXaaHis sequence motifs in a four-helix bundle that provide the six amino-acid ligands for the di-iron... 

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