Nonheme Fe(II) oxygenases: structure-activity relationships

Mononuclear nonheme iron active sites are enzymic key structures to bring about the reaction of dioxygen with organic substrates, a process, which is crucial for life. The respective oxygen utilizing enzymes, therefore, are ubiquitous in nature playing central roles in the environmental degradation of xenobiotics as well as in human metabolism. The catalyzed reactions cannot easily be mimicked by non-enzymatic, chemical models. Due to their great importance in physiological processes and their supremacy in bringing about a variety of very complex oxygen utilizing reactions, which comprise cleavage of C-C single- and double-bonds, hydroxylation, decarboxylation and even carbon-heteroatom bond formation, mononuclear nonheme iron enzymes are a target of intense research. Structural data reveal that despite the apparent catalytic diversity, the organisation of the metal binding site shows only few pirinciple structures. A common metal binding motif, a facial triad of two histidines and one carboxylate, was found to link numerous, diverse enzymes to one big superfamily. Initially, this ligand pattern appeared to be mandatory, in recent years, however, a number of dioxygenases have been discovered which have the same principle active site geometry, but show some variation of the metal binding amino-acids employed. This poses the question of the actual impact of the iron`s first coordination shell on enzyme catalysis and particularly on the reactivity of the metal-centre towards dioxygen. While the nonheme Fe(II) dependent enzymes apparently share the same catalytic concept, which is reduction of molecular oxygen by the metal-substrate complex, the fate of the transient peroxidate intermediate determines the actual reaction catalyzed and consequently accounts for the versatility of reactions catalyzed by this enzyme grouping. The pathway of peroxidate decay, however, is governed by the intrinsic properties of the substrate and by the enzyme`s second coordination sphere. In this project we will perform mechanistic studies on nonheme Fe(II) dependent dioxygenases that show remarkable structural similarity but catalyze rather diverse reactions, C-C bond cleavage or stereospecific hydroxylations, respectively. We will investigate the impact of the major determinants of the enzyme mechanism, namely substrate structure and first and second coordination shell, on the particular steps of catalysis. This work will significantly contribute to a profound understanding of (i) the reactivity of nonheme Fe(II) centres towards dioxygen, which is a major research field of bioinorganic chemistry, and (ii) the impact of the active site environment on the subsequent reaction pathway of these fascinating biocatalysts.

Mononuclear nonheme iron active sites are enzymic key structures to bring about the reaction of dioxygen with organic substrates, a process, which is crucial for life. The respective oxygen utilizing enzymes, therefore, are ubiquitous in nature playing central roles in the environmental degradation of xenobiotics as well as in human metabolism. The catalyzed reactions cannot easily be mimicked by non-enzymatic, chemical models. Due to their great importance in physiological processes and their supremacy in bringing about a variety of very complex oxygen utilizing reactions, which comprise cleavage of C-C single- and double-bonds, hydroxylation, decarboxylation and even carbon-heteroatom bond formation, mononuclear nonheme iron enzymes are a target of intense research. Structural data reveal that despite the apparent catalytic diversity, the organisation of the metal binding site shows only few pirinciple structures. A common metal binding motif, a facial triad of two histidines and one carboxylate, was found to link numerous, diverse enzymes to one big superfamily. Initially, this ligand pattern appeared to be mandatory, in recent years, however, a number of dioxygenases have been discovered which have the same principle active site geometry, but show some variation of the metal binding amino-acids employed. This poses the question of the actual impact of the iron`s first coordination shell on enzyme catalysis and particularly on the reactivity of the metal-centre towards dioxygen. While the nonheme Fe(II) dependent enzymes apparently share the same catalytic concept, which is reduction of molecular oxygen by the metal-substrate complex, the fate of the transient peroxidate intermediate determines the actual reaction catalyzed and consequently accounts for the versatility of reactions catalyzed by this enzyme grouping. The pathway of peroxidate decay, however, is governed by the intrinsic properties of the substrate and by the enzyme`s second coordination sphere. In this project we will perform mechanistic studies on nonheme Fe(II) dependent dioxygenases that show remarkable structural similarity but catalyze rather diverse reactions, C-C bond cleavage or stereospecific hydroxylations, respectively. We will investigate the impact of the major determinants of the enzyme mechanism, namely substrate structure and first and second coordination shell, on the particular steps of catalysis. This work will significantly contribute to a profound understanding of (i) the reactivity of nonheme Fe(II) centres towards dioxygen, which is a major research field of bioinorganic chemistry, and (ii) the impact of the active site environment on the subsequent reaction pathway of these fascinating biocatalysts.