Compound I formation mechanisms

DET calculations on the hyperfine coupling constants of ethyl imidazole as a model for histidine support experimental results that the preferred histidine radical is formed by OH addition at the C5 position [00JPC(A)9144]. The reaction mechanism of compound I formation in heme peroxidases has been investigated at the B3-LYP level [99JA10178]. The reaction starts with a proton transfer from the peroxide to the distal histidine and a subsequent proton back donation from the histidine to the second oxygen of the peroxide (Scheme 8). 

Fig. 18. Mechanisms of compound I formation in type B catalases (based on yeast CCP) (see also Section IV,F and Fig. 7) (A) type A catalases (B) and chloroperoxidase (C).

The mechanisms for the rednction of compounds I and II are less well nnderstood than the mechanism of compound I formation, although a number of suggestions have been presented in the literature (24). It is clear from site-directed mutagenesis studies that Arg38 and His42 are also important in the rednction steps, although their precise role has been difficnlt to define. A detailed mechanism for snbstrate oxidation by plant peroxidases has been proposed, based on data from the crystal... 

The detailed mechanism of P aeruginosa CCP has been studied by a combination of stopped-flow spectroscopy (64, 65, 84, 85) and paramagnetic spectroscopies (51, 74). These data have been combined by Foote and colleagues (62) to yield a quantitative scheme that describes the activation process and reaction cycle. A version of this scheme, which involves four spectroscopically distinct intermediates, is shown in Fig. 10. In this scheme the resting oxidized enzyme (structure in Section III,B) reacts with 1 equiv of an electron donor (Cu(I) azurin) to yield the active mixed-valence (half-reduced) state. The active MV form reacts productively with substrate, hydrogen peroxide, to yield compound I. Compound I reacts sequentially with two further equivalents of Cu(I) azurin to complete the reduction of peroxide (compound II) before returning the enzyme to the MV state. A further state, compound 0, that has not been shown experimentally but would precede compound I formation is proposed in order to facilitate comparison with other peroxidases. 

Chen H. Hirao H. Derat E. Schlichting I. Shaik S. Quantum mechanical/molecular mechanical study on the mechanisms of compound I formation in the catalytic cycle of chloroperoxidase an overview on heme enzymes. J. Phys. Chem. B 2008, 112, 9490-9500. 

By contrast, the catalytic site responsible for the halogenation, hydroxylation, and other (two-electron) oxygenation reactions has been better, although not completely, characterized by X-ray crystallography of CPO complexed with several substrates (such as iodide/bromide and cyclopentane-1,3-dione) and other compounds (such as carbon monoxide, thiocyanate, nitrate, acetate, formate and, in a ternary complex, with dimethylsulfoxide and cyanide) [88, 90]. The above substrates bind at the distal side of heme, and the corresponding structures were also useful to establish the mechanism of Compound I formation as discussed above [90]. 

Hiner ANP, Raven EL, Thomeley RNF et al (2002) Mechanisms of compound I formation in heme peroxidases. J Inorg Biochem 91 27-34... 

Wirstam M, Blomberg MRA, Siegbahn PEM (1999) Reaction mechanism of compound I formation in heme peroxidases a density functional theory study. J Am Chem Soc 121 10178-10185... 

Derat E, Shaik S (2006) The Poulos-Kraut mechanism of Compound I formation in horseradish peroxidase a QM/MM study. J Phys Chem B 110 10526—10533... 

Jones P, Dunford HB (2005) The mechanism of Compound I formation revisited. J Inorg Biochem 99 2292-2298... 

Fig. 10.5. Push-pull mechanism for Compound I formation in peroxidases (adapted from [12] and [63]). Distal residues (Arg and His) work together to cleave the 0-0 bond, while proximal residues (His and Asp) assist by supplying electron density.

G. Plant and Mammalian Peroxidase Superfamilies Mechanisms of Compound I Formation Endogenous Reduction of Peroxidase Intermediates Exogenous Reduction of Peroxidase Intermediates... 

Fe =0 moiety to Fe" =0 thus, one oxidizing equivalent remained at the heme iron and one was stored on the polypeptide as an amino acid radical in CCP compound I. The formation of Fe =0 has not been validated experimentally for CCP, or any other heme peroxidase, possibly because of its rapid intramolecular reduction to Fe =0. The formation of Fe =0 is not, however, a requirement in the mechanisms of compound I formation discussed later, because the porphyrin or protein (via the porphyrin. Section IV) could directly donate an electron to the peroxide. 

Similar mechanisms of compound I formation are believed to hold for plant and fungal peroxidases. Five of the nine conserved residues in the plant peroxidase superfamily (Section II,G) are at the active site, and these residues in CCP (Arg48, His52, Asn82, Hisl75, Asp235) are shown in Fig. 2. Elucidation of the X-ray structures of LIP (Fig. 

Scheme V. Proposed mechanism for CCP compound I formation, (a) The native enzymes (b) the activated complex with the distal histidine operating as an acid-base catalyst and the active site arginine stabilizing a developing negative charge on RO-OFe (c) the hypothetical oxene intermediate (d) Compound I after the intramolecular electron rearrangement of (c) to give Fe(IV) and a hee radical, X.

Very recently, Rietjens and co-workers proposed an alternative mechanism, reversible compound I formation, to explain more than 90% 0-incorporation from bulk water into... 

Figure 16.2 Proposed mechanism for compound I formation in chioroperoxidase [25]. The deprotonated active site Giu-183 first abstracts a proton from the incoming hydrogen peroxide. The generated hydroperoxo anion then binds to the heme yielding...

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