Carboxylate‐Bridged Dinuclear Active Sites in Oxygenases: Diiron, Dimanganese, or is Heterodinuclear Better?

Abstract

bioinorganic chemistry · enzymes · iron · manganese · metalloproteinsCarboxylate-bridged diiron centers are a frequently observed structural motif in biological systems, and the corresponding enzymes catalyze a wide range of important reactions. Within this class of enzymes, a highly interesting family of diiron proteins is characterized by an eye-catching feature in their secondary structure: The dinuclear metal site is localized between a bundle of four a helices (four-helix bundle proteins) that provide coordinating amino acid residues (histidine, glutamate, and/or aspartate) for the binding of metal ions, which are usually bridged by proteinbased carboxylate functionalities and/or oxo ligands (water molecules, hydroxo or oxo ions). It is particularly interesting that the members of this protein family, despite their similarly structured metal sites, catalyze a wide variety of biological processes that appear at first sight to be highly different. However, a closer look at the reactions reveals that most of these processes are based on the common reactivity of the enzymes towards molecular oxygen, which is activated and reduced by the dinuclear metal site. Fascinating and intensely studied examples of this family are the soluble methane monooxygenases (sMMOs), [1] the soluble fatty acid desaturases, [2] and the ribonucleotide reductases (RNRs; Scheme 1). [3] The similar reactivity towards oxygen, the highly conserved structure of the dinuclear metal site, and a protein environment with four-helix bundles has led to the belief that this family of enzymes has evolved from a common ancient primitive oxidase. The original task of this oxidase might have been the fast and reliable reduction of molecular oxygen, thus protecting the cell against oxidative stress caused by the transition from a reducing to an oxidizing atmosphere about 2.5 billion years ago. This hypothesis is supported by a recent study in which the replacement of a single amino acid in a soluble fatty acid desaturase led to a total loss of desaturase acitivity and a simultaneous increase in oxidase activity. [4] Very recently, two new members of this protein family were isolated from certain bacteria and found to be quite different from their prominent relatives in various aspects. These unusual enzymes are the ribonucleotide reductase of Chlamydia trachomatis [5] and the N-oxygenase AurF of Streptomyces thioluteus.[6] Interestingly, the unambiguous assignment of the identity of the active metal sites in these systems still remains an open question. In particular, it is not yet entirely clear whether these enzymes are homometallic diiron or dimanganese systems or even contain heterometallic MnFe centers as their active sites. The elucidation of the chemical identity and reactivity of these dinuclear metal sites represents a highly exciting and challenging task in the field of modern bioinorganic chemistry.It is believed that the deoxygenation of ribonucleotides catalyzed by ribonucleotide reductases is initiated by the formation of a protein-based t...

Density Functional Theory Study of the Manganese-Containing Ribonucleotide Reductase from Chlamydia trachomatis: Why Manganese Is Needed in the Active Complex

“…The small energy difference makes the assignment of position 1 for Mn rather uncertain. From arguments about the proximity of position 1 to the electron transfer chain and the observed change exclusively of the oxidation state of MnIV in the activated state, Mn in position 1 is consistent with experiments, as concluded by Roth et al (38) However, for a complete picture, some of the calculations below were also made on a model with Mn in position 2. The difference in energetics between having a higher oxidation state on Fe instead of Mn is larger, 14.4 kcal mol -1 , showing that Mn(IV)Fe(III) is much more stable than Mn(III)Fe(IV), consistent with experiments (15,17).…”

Metal use in ribonucleotide reductase R2, di-iron, di-manganese and heterodinuclear—an intricate bioinorganic workaround to use different metals for the same reaction

“…95,[96][97][98][99][100][101] For recent reviews see. [102][103][104][105] Notably, it was shown that the reconstitution reaction proceeds via a Mn(IV)-Fe(IV) Intermediate state. 106 This is interesting because the Fe(IV)-Fe(IV) intermediate has not been observed in standard R2 proteins while it has been observed in 2-electron oxidases such as MMO.…”

NMR spectroscopic investigations on the successive implementation of nickel and zinc ions to a NacNac‐dibenzofuran‐Br ligand precursor

“…[5][6][7][8] This principle is often exploited for natural small molecule conversion in enzymes. [9][10][11][12] However, the synthesis of heterodinuclear complexes from mononuclear precursors presents a special challenge due to possible disproportionation and selectivity problems resulting in mixtures of symmetric and asymmetric complexes. One way to steer heterodinuclearity is to utilize a ligand backbone with two different binding sites [13] (for the combination Ni/Zn, which is of relevance here see e.g.…”