Hemoprotein enzymes

These reactions are thought to involve oxidation of the agents, in the case of the hydrazines after initial oxidation to the diazenes, to free radicals that react with the heme group (Fig. 25). Explicit evidence exists for the isoporphyrin intermediate (bottom right structure. Fig. 25) in the case of cyclopropanol hydrate (Wiseman et al., 1982) and the alkylhydrazines (Ator et al., 1987, 1989). 

Horseradish peroxidase can be inactivated by protein as well as heme modifications. The reaction of horseradish peroxidase with phenylhydrazine is instructive in this regard (Ator and Ortiz de Montellano, 1987). Enzyme inactivation correlates well with covalent binding of 2 equivalents of radiolabeled phenylhydrazine but is associated with conversion of only a small fraction of the prosthetic group to the meso-phenyl adduct. Covalent binding of a metabolite of phenylhydrazine to the protein is therefore primarily responsible for enzyme inactivation, although the identity of the reactive species and the site at which it reacts are not known. The factors that determine whether the heme group (e.g., methylhydrazine, sodium azide) or the protein (e.g., phenylhydrazine) is the primary site of the inactivation reaction also remain elusive. 

Thyroid peroxidase and lactoperoxidase, but not horseradish peroxidase (Petry and Eling, 1987), are inactivated by heterocyclic sulfur compounds such as propylthiouracil and l-methylbenzimidazoline-2-thione (Fig. 26) (Neary et al., 1984 Ohtaki et al., 1985 Doerge, 1986). The inactivation of thyroid peroxidase 

The oxidation of alkyl and aryl hydrazines or 4-alkyl-3,5-bis(carbethoxy)-2,6-dimethyl-l,4-dihydropyridines by cytochrome F-450 results in addition of the 

The details of heme N-alkylation by alkyl radicals are unclear because no intermediates have been detected in the reaction. However, the fact that reaction 

---

Cytochrome P450 (CYP) mono-oxygenases, also called mixed function oxidases, are versatile hemoprotein enzymes that catalyze the cleavage of molecular oxygen to incoiporate one oxygen atom into a substrate molecule and one atom into water [1]. The general stoichiometry of the reaction is as follows (S-H, substrate) ... 

Cytochrome F450 represents a huge family, containing 30 to 200 genes (Gonzalez et oL, 1986) encoding hemoprotein enzymes that possess catalytic activity toward thocisands of substrates. These enzymes... 

Fig. 21. Typical intermediates in hemoprotein enzyme active sites. The iron protoporphyrin IX cofactor (heme) forms dioxygen adducts termed oxy-species. In the course of oxygen activation and catalytic redox transformations, the oxy form can be consecutively converted into hydroperoxo- and oxo-type intermediates, which are usually referred to as compound 0, compound I, and compound II. Reproduced with permission from Ref (183). Copyright Nature Publishing Group.

TPO is a hemoprotein enzyme tvith binding sites for both iodine and tyrosine. In model systems, TPO has no catalytic activity in the absence of H2O2. TPO degrades H2O2 in a catalase-like reaction releasing O2. Several iodination intermediates were postulated for this reaction, for instance TPO-bound iodinium (U) andTPO-bound hypoiodite (I ). 

---