Oxygen activation by mononuclear nonheme iron dioxygenases involved in the degradation of aromatics

Abstract

Molecular oxygen is utilized in numerous metabolic pathways fundamental for life. Mononuclear nonheme iron-dependent oxygenase enzymes are well known for their involvement in some of these pathways, activating O₂ so that oxygen atoms can be incorporated into their primary substrates. These reactions often initiate pathways that allow organisms to use stable organic molecules as sources of carbon and energy for growth. From the myriad of reactions in which these enzymes are involved, this perspective recounts the general mechanisms of aromatic dihydroxylation and oxidative ring cleavage, both of which are ubiquitous chemical reactions found in life-sustaining processes. The organic substrate provides all four electrons required for oxygen activation and insertion in the reactions mediated by extradiol and intradiol ring-cleaving catechol dioxygenases. In contrast, two of the electrons are provided by NADH in the cis-dihydroxylation mechanism of Rieske dioxygenases. The catalytic nonheme Fe center, with the aid of active site residues, facilitates these electron transfers to O₂ as key elements of the activation processes. This review discusses some general questions for the catalytic strategies of oxygen activation and insertion into aromatic compounds employed by mononuclear nonheme iron-dependent dioxygenases. These include: (1) how oxygen is activated, (2) whether there are common intermediates before oxygen transfer to the aromatic substrate, and (3) are these key intermediates unique to mononuclear nonheme iron dioxygenases?

Keywords: Catalytic strategies; Crystal structure; High-valent iron species; Metabolism; Nonheme iron enzymes; Oxidative degradation; Reactive oxygen species; Ring-cleaving dioxygenase; Spectroscopy.

Figure 1

Proposed catalytic routes of Rieske dioxygenases through hemolysis (upper) and heterolysis (bottom) of O-O bond.

Figure 2

Distinct natural catechol dioxygenase activities. (A) Extradiol and intradiol cleavges, (B) the alkylperoxo intermediate structurally characterized in the extradiol dioxygenase 2,3-HPCD (from 2IGA.pdb), and (C) the structure of the anhydride intermediate in the intradiol dioxygenase 3,4-PCD (from 4WHR.pdb).

Figure 3

The catalytic mechanism of extradiol ring-cleaving dioxygenases

Figure 4

The catalytic cycle of intradiol ring-cleaving dioxygenases.

Figure 5

Compariso of the Fe-bound peroxo interemdiates of mononuclear nonheme Fe dioxygenases with the analogous intermediates of a nonheem Fe-dependent thiol dioxygenase and heme-dependent tryptophan 2,3-dioxygenase. Key catalytic intermediates of alkylperoxo intermediate found in extradiol dioxygenase (1) and intradiol dioxygenase (2), a hydroperoxo intermediate in the catalytic route of Rieske dioxygenases (3), a putative persulfenate intermediate in thiol dioxygenase (4), an alkylperoxo radical intermediate proposed for the Rieske dioxygenases (5) and an analogous 2-indolenylperoxo radical intermediate in the catalytic cycle of heme-dependent tryptophan 2,3-dioxygenase (6).