Iron oxygenase

Nothing is known about the identity of the iron species responsible for dehydrogenation of the substrate. Iron-oxo species such as FeIV=0 or Fem-OOH are postulated as the oxidants in most heme or non-heme iron oxygenases. It has to be considered that any mechanistic model proposed must account not only for the observed stereochemistry but also for the lack of hydroxylation activity and its inability to convert the olefinic substrate. Furthermore, no HppE sequence homo-logue is to be found in protein databases. Further studies should shed more light on the mechanism with which this unique enzyme operates. 

The alkane hydroxylase belongs to a family of nonheme iron oxygenases. There is some structural similarity between the nucleotide sequence of the integral membrane alkane hydroxylase and... 

Rosche B, B Tshisuaka, B Hauer, F Lingens, S Fetzner (1997) 2-Oxo-l,2-dihydroquinoline 8-monooxygen-ase phylogenetic relationship to other multicomponent nonheme iron oxygenases. J Bacterial 179 3549-3554. 

The alkane hydroxylase belongs to a family of nonheme iron oxygenases. There is some structural similarity between the nucleotide sequence of the integral-membrane alkane hydroxylase and the subunits of the monooxygenase encoded by xylA and xylM in the TOL plasmid that are involved in hydrox-ylation of the methyl groups in toluene and xylene in Pseudomonas putida PaWl (Suzuki et al. 1991). 

These enzymes catalyze a variety of oxidative reactions in natural product biosynthesis with two C—Hhydroxylation examples shown in Figure 13.24 [72,73]. It should be noted thatC—H activation by nonheme iron oxygenases, such as aromatic dioxygenases, is an important pathway in degradation of aromatics into m-dibydrodiols, which are important chiral building blocks for chemical synthesis [74,75]. 

Rosche, B. Tshisuaka, B. Hauer, B., et al., 2-Oxo-l,2-Dihydroquinoline 8-Monooxygenase, Phylogenetic Relationship to other Multicomponent Nonheme Iron Oxygenases. J. Bacteriol, 1997. 179(11) pp. 3549-54. 

The 2-His-l-Carboxylate Facial Triad in Non-Heme Iron Oxygenases 101... 

In the past decade there has been an enormous progress in the field of non-heme iron oxygenases. Almost annually, new reviews are published showing clearly an increasing interest in this field (1-18). 

The number of known or presumed mononuclear, non-heme iron oxygenases and related enzymes continues to grow. This is due to intensive biochemical research and especially based on sequence data derived from genome research projects i.14). For several of these enzymes structural data are available by now from protein crystallography (12-14). In many of the iron oxygenases the iron is facially bound by two histidines and one carboxylate donor, either glutamic acid or aspartic acid. Thus, the term 2-His-l-carboxylate facial triad has been introduced by L. Que Jr. for this motif (19). 

Scheme 4. Mechanism of the 2-oxoglutarate dependent iron oxygenases (8).

Inhibitors for 2-OG dependent iron oxygenases thus have a huge pharmaceutical potential as future drugs. In particular inhibitors for prolyl 4-hydroxylase could help to control collagen production (34,36). Such an inhibitor should mimic the k 0, 0 chelate coordination of 2-OGs but should not react with O2. A -Oxalylglycine (Fig. 3) is such an inhibitor for prolyl 4-hydroxylase (IC50 = 3 pM) (34,36). 

To detect any functional activity of complex 6 with O2, the air-exposed solution was acidified and analyzed by GC. Unfortunately, we have not been able to detect any benzoic acid until now, which should have been formed from benzoylformic acid and O2 in analogy to the catalytic cycle of the 2-OG dependent iron oxygenases. 

Then later in an aerobic world with mainly iron(III) both, zinc peptidases and iron oxygenases, evolved from these ancestors. Today nature mainly uses zinc centers in metalloenzymes for the hydrolyses of peptide bonds (99,J00). In the commonly accepted mechanism for zinc peptidases, zinc(II) has two tasks It polarizes the carbonyl functionality of the peptide bond that is going to be cleaved and it supports the deprotonation of the coordinated water nucleophile. 

Scheme 7.22 Non-heme iron oxygenase in biosynthesis of clavulanic acid.

The common motif shared by non-heme iron oxygenases contains an active site, where two histidines and one carboxylate occupy one face of the Fe(ll) coordination sphere. These enzymes catalyze a variety of oxidative modification of natural products. For example, in the biosynthesis of clavulanic acid, clavaminic acid synthase demonstrates remarkable versatility by catalyzing hydroxylation, oxidative ring formation and desaturation in the presence of a-ketoglutarate (eq. 1 in Scheme 7.22) [80]. The same theme was seen in the biosynthesis of isopenicillin, the key precursor to penicillin G and cephalosporin, from a linear tripeptide proceeded from a NRPS, where non-heme iron oxygenases catalyze radical cyclization and ring expansion (eq. 2 in Scheme 7.22) [81, 82]. 

NADP(H) [83, 84]. In addition to dioxygenation, non-heme iron oxygenases can perform monohydroxylation as in the synthesis of L-DOPA from L-tyrosine in mammalian species [85]. 

Julsing MK, Comelissen S et al (2008) Heme-iron oxygenases powerful industrial biocatalysts Curr Opin Chem Biol 12 177-186... 

Lawrence Que Synthesis of a nonheme ferryl complex, an analogue of nonheme iron oxygenase active intermediates... 

Soluble methane monooxygenase (sMMO) is the best studied binuclear non-heme iron oxygenase enzyme, largely due... 

As mentioned, many non-heme iron enzymes also catalyze oxidase-type reactions, such as desaturation, in biological systems (7). Similar to the non-heme iron oxygenases, the reactions are thought to proceed through an Fe =0 intermediate. Two examples of enzymes that catalyze biologically interesting oxidase reactions are isopenicillin N-synthase (IPNS) and 1-aminocyclopropane-l-carboxylate oxidase (ACCO). 

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