Excessive hydrogen peroxide is harmful for almost all cell components, so its rapid and efficient removal is of essential importance for aerobically living organisms. Conversely, hydrogen peroxide acts as a second messenger in signal-transduction pathways. H₂O₂ is degraded by peroxidases and catalases, the latter being able both to reduce H₂O₂ to water and to oxidize it to molecular oxygen. Nature has evolved three protein families that are able to catalyze this dismutation at reasonable rates. Two of the protein families are heme enzymes: typical catalases and catalase–peroxidases. Typical catalases comprise the most abundant group found in Eubacteria, Archaeabacteria, Protista, Fungi, Plantae, and Animalia, whereas catalase–peroxidases are not found in plants and animals and exhibit both catalatic and peroxidatic activities. The third group is a minor bacterial protein family with a dimanganese active site called manganese catalases. Although catalyzing the same reaction (2 H₂O₂→ 2 H₂O+ O₂), the three groups differ significantly in their overall and active-site architecture and the mechanism of reaction. Here, we present an overview of the distribution, phylogeny, structure, and function of these enzymes. Additionally, we report about their physiologic role, response to oxidative stress, and about diseases related to catalase deficiency in humans.

Myeloperoxidase (MPO), a member of the haem peroxidase‐cyclooxygenase superfamily, is abundantly expressed in neutrophils and to a lesser extent in monocytes and certain type of macrophages. MPO participates in innate immune defence mechanism through formation of microbicidal reactive oxidants and diffusible radical species. A unique activity of MPO is its ability to use chloride as a cosubstrate with hydrogen peroxide to generate chlorinating oxidants such as hypochlorous acid, a potent antimicrobial agent. However, evidence has emerged that MPO‐derived oxidants contribute to tissue damage and the initiation and propagation of acute and chronic vascular inflammatory disease. The fact that circulating levels of MPO have been shown to predict risks for major adverse cardiac events and that levels of MPO‐derived chlorinated compounds are specific biomarkers for disease progression, has attracted considerable interest in the development of therapeutically useful MPO inhibitors. Today, detailed information on the structure of ferric MPO and its complexes with low‐ and high‐spin ligands is available. This, together with a thorough understanding of reaction mechanisms including redox properties of intermediates, enables a rationale attempt in developing specific MPO inhibitors that still maintain MPO activity during host defence and bacterial killing but interfere with pathophysiologically persistent activation of MPO. The various approaches to inhibit enzyme activity of MPO and to ameliorate adverse effects of MPO‐derived oxidants will be discussed. Emphasis will be put on mechanism‐based inhibitors and high‐throughput screening of compounds as well as the discussion of physiologically useful HOCl scavengers.British Journal of Pharmacology(2007)152, 838–854; doi:10.1038/sj.bjp.0707358; published online 25 June 2007

Four heme peroxidase superfamilies (peroxidase-catalase, peroxidase-cyclooxygenase, peroxidase-chlorite dismutase and peroxidase-peroxygenase superfamily) arose independently during evolution, which differ in overall fold, active site architecture and enzymatic activities. The redox cofactor is heme b or posttranslationally modified heme that is ligated by either histidine or cysteine. Heme peroxidases are found in all kingdoms of life and typically catalyze the one- and two-electron oxidation of a myriad of organic and inorganic substrates. In addition to this peroxidatic activity distinct (sub)families show pronounced catalase, cyclooxygenase, chlorite dismutase or peroxygenase activities. Here we describe the phylogeny of these four superfamilies and present the most important sequence signatures and active site architectures. The classification of families is described as well as important turning points in evolution. We show that at least three heme peroxidase superfamilies have ancient prokaryotic roots with several alternative ways of divergent evolution. In later evolutionary steps, they almost always produced highly evolved and specialized clades of peroxidases in eukaryotic kingdoms with a significant portion of such genes involved in coding various fusion proteins with novel physiological functions.

Myeloperoxidase (MPO) is a major neutrophil protein and may be involved in the nitration of tyrosine residues observed in a wide range of inflammatory diseases that involve neutrophils and macrophage activation. In order to clarify if nitrite could be a physiological substrate of myeloperoxidase, we investigated the reactions of the ferric enzyme and its redox intermediates, compound I and compound II, with nitrite under pre-steady state conditions by using sequential mixing stopped-flow analysis in the pH range 4–8. At 15 °C the rate of formation of the low spin MPO-nitrite complex is (2.5 ± 0.2) × 10⁴ m ^{− 1} s^{− 1}at pH 7 and (2.2 ± 0.7) × 10⁶ m ^{− 1} s^{− 1}at pH 5. The dissociation constant of nitrite bound to the native enzyme is 2.3 ± 0.1 mm at pH 7 and 31.3 ± 0.5 μm at pH 5. Nitrite is oxidized by two one-electron steps in the MPO peroxidase cycle. The second-order rate constant of reduction of compound I to compound II at 15 °C is (2.0 ± 0.2) × 10⁶ m ^{− 1}s^{− 1} at pH 7 and (1.1 ± 0.2) × 10⁷ m ^{− 1}s^{− 1} at pH 5. The rate constant of reduction of compound II to the ferric native enzyme at 15 °C is (5.5 ± 0.1) × 10² m ^{− 1}s^{− 1} at pH 7 and (8.9 ± 1.6) × 10⁴ m ^{− 1}s^{− 1} at pH 5. pH dependence studies suggest that both complex formation between the ferric enzyme and nitrite and nitrite oxidation by compounds I and II are controlled by a residue with a pK _a of (4.3 ± 0.3). Protonation of this group (which is most likely the distal histidine) is necessary for optimum nitrite binding and oxidation.