Versatility of biological non-heme Fe(II) centers in oxygen activation reactions

Abstract

Oxidase and oxygenase enzymes allow the use of relatively unreactive O 2 in biochemical reactions. Many of the mechanistic strategies employed in nature for this key reaction are represented within the 2-His-1-carboxylate facial triad family of non-heme Fe(II) containing enzymes. The open face of the metal coordination sphere opposite the three endogenous ligands participates directly in the reaction chemistry. Here, data from several studies are presented showing that reductive O 2 activation within this family is initiated by substrate (and in some cases co-substrate or cofactor) binding, which then allows coordination of O 2 to the metal. From this starting point, both the O 2 activation process and the reactions with substrates diverge broadly. The reactive species formed in these reactions have been proposed to encompass four oxidation states of iron and all forms of reduced O 2 as well as several of the reactive oxygen species that derive from O-O bond cleavage.Dioxygen serves at least three quite different roles that profoundly impact aerobic life. The most commonly appreciated role is to serve as the terminal electron acceptor in processes such as oxidative phosphorylation that yield the central energy-rich molecules used throughout metabolism. The second, no less important role is to serve as the source for many of the oxygen atoms found in the essential molecules of biological systems such as steroid hormones, aromatic amino acids, neurotransmitters, signalling molecules, and regulatory factors 1 . Also, processes operating on a global scale, such as the recovery of the enormous quantities of carbon sequestered as lignin in plant life or the oxidation of the billions of tons of methane generated by anaerobes before it can enter the atmosphere, also involve oxygen incorporation from O 2 2 ,3 . On a more local scale, biodegradation of both aliphatic and aromatic toxic compounds often begins with the incorporation of oxygen 4 . The third, and least appreciated role played by dioxygen in aerobic organisms involves neither energy conversion nor oxygen incorporation. Rather, some enzymes can convert dioxygen to alternative forms that are, in effect, highly specialized reagents that are used to catalyze the synthesis of important biomolecules. An excellent example of the latter role for O 2 is the biosynthesis of penicillintype antibiotics 5,6 , which is discussed in more detail later in this review.Dioxygen is an attractive reagent for use in a biological system because its high potential reactivity is held in check by its molecular structure. The triplet ground state of O 2 that results from the presence of two unpaired electrons in degenerate molecular orbitals makes the direct reaction with singlet molecules, the spin-paired state of most potential reaction partners, a forbidden process 7 . The central question that has faced chemists and biochemists for the half Competing Interests StatementThe authors declare no competing financial interests. Of course, the answers to this question are of fundam...

Dioxygenases in Burkholderia ambifaria and Yersinia pestis that hydroxylate the outer Kdo unit of lipopolysaccharide

“…1A) with mechanistic similarity to LpxO (16,17), the Fe 2þ /α-ketoglutarate/O 2 -dependent dioxygenase that generates the secondary S-2-hydroxymyristate chain of Salmonella lipid A. We therefore searched for genes that met three criteria: (i) their presence in appropriate strains of Burkholderia and Yersinia, but not E. coli or Salmonella; (ii) their clustering with other LPS biosynthetic genes; and (iii) the presence of the iron-binding motif HXðD∕EÞX n>40 H in the predicted protein (18,19). The bamb_0774 gene of Burkholderia ambifaria encodes a protein of 294 amino acid residues and is located between the kdtA(waaA) and waaC(rfaC) genes (Fig.…”

“…Fe 2þ /α-ketoglutarate/O 2 -dependent dioxygenases constitute a large and diverse family of mononuclear nonheme iron enzymes (18,19). Crystal structures of different α-ketoglutarate-dependent dioxygenases have revealed a common architecture (18,19).…”

“…Crystal structures of different α-ketoglutarate-dependent dioxygenases have revealed a common architecture (18,19). Whereas these proteins may show low overall sequence similarity, most α-ketoglutarate-dependent dioxygenases share the HXðD∕EÞX n HX m ðR∕KÞXS motif (in which n ¼ 50-70 and m ¼ 10, n ¼ 138-207 and m ¼ 10-13, or n ¼ 72-101 and m ¼ 10) (18, 19).…”

“…The enzyme that catalyzes Kdo hydroxylation, termed KdoO, is a unique member of the Fe 2þ /α-ketoglutarate/O 2 -dependent dioxygenase family (18,19). The KdoO structural gene (Fig.…”

Insight into the mechanism of an iron dioxygenase by resolution of steps following the Fe IV ═O species

“…Many heme and non-heme iron oxygenases are believed to share highly oxidized iron-oxo species as central elements in their reaction mechanisms (1,2). Several transient oxygen intermediates have been studied extensively in heme enzymes, including compound I-type species of cytochrome P450s (3), but the intermediates occurring during substrate oxygenation have not been directly observed.…”