Mammalian Heme Peroxidases

Diverse Roles in Health and Disease

Clare Hawkins, William M Nauseef, Clare Hawkins, William M Nauseef

• Publisher: CRC Press
• Year: 2021
• ISBN:
  9781000450637
• Edition: 1
• Topic: Medicina
• Subtopic: Biochimica in medicina

Mammalian heme peroxidase enzymes play a critical role in innate immune responses and disease prevention. The formation of potent chemical oxidants is essential to this protective physiologic activity in immunity. Although highly beneficial in the context of immune defense, it is now well established that peroxidases and their overproduction of oxidants contribute to the initiation and persistence of many chronic inflammatory conditions in the cardiovascular, neurologic, respiratory, renal, and gastrointestinal systems. Peroxidasins, a protein family related to heme peroxidases, play a novel role in tissue biogenesis and matrix assembly, which are also attracting attention in different pathological contexts. Given the diverse roles of mammalian heme peroxidases and the breadth and incidence of pathologies associated with these enzymes, there has been significant interest in modulating peroxidase activity as a therapeutic strategy. This book highlights recent developments in our understanding of the chemistry, biochemistry and biological roles of mammalian peroxidases and their associated oxidants, their involvement in both innate immunity and chronic inflammatory disease in a variety of end organs, and potential therapeutic approaches to modulate and prevent damaging reactions.

Key Features

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• Structure and biosynthesis of mammalian peroxidases

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• Reactivity of hypohalous acids with biological substrates

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• Peroxidases in innate immunity

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• Peroxidases in human pathology
• Modulation of peroxidase-induced biological damage

PART ONE Introduction to Mammalian Heme Peroxidases

Chapter One Evolution, Structure and Biochemistry of Human Peroxidases

Paul G. Furtmüller

University of Natural Resources and Life Sciences

Marcel Zámocký

University of Natural Resources and Life Sciences Slovak Academy of Sciences

Stefan Hofbauer

University of Natural Resources and Life Sciences

Christian Obinger

University of Natural Resources and Life Sciences

DOI: 10.1201/9781003212287-2

Contents

1. Abbreviations
2. Heme Peroxidases
3. Evolution and Functions of Peroxidases from the Peroxidase-Cyclooxygenase Superfamily
4. Structure of the Peroxidase Domain of Human Peroxidases
5. Biophysical Properties of Human Peroxidases
6. Catalytic Properties of Human Peroxidases
7. Conclusion
8. Acknowledgements
9. References

Abbreviations

DdPoxA

Peroxidase A from Dictyostelium discoideum

E°′

Standard reduction potential

EPO

Eosinophil peroxidase

HRP

Horseradish peroxidase

LPO

Lactoperoxidase

LspPOX

Peroxidase from the cyanobacterium Lyngbya sp. PCC 8105

MPO

Myeloperoxidase

proMPO

Promyeloperoxidase

PXDN

Human peroxidasin 1

RR

Resonance Raman

TPO

Thyroid peroxidase

Heme Peroxidases

Heme peroxidases use heme b or posttranslationally modified heme as a redox cofactor to catalyse the hydrogen peroxide–mediated one- and two-electron oxidation of a myriad of molecules, including aromatic molecules (e.g. coniferyl alcohol or tyrosine), cations (e.g. Mn²⁺), anions (e.g. ascorbate or halides) or even proteins (e.g. cytochrome c). During turnover, H₂O₂ is reduced to water and one-electron donors (AH₂) are oxidized to the respective radicals (^•AH) (Reaction 1), whereas two-electron donors such as halides (X⁻) are oxidized to the corresponding hypohalous acids (HOX) (Reaction 2). Besides these peroxidatic reactivities, very few heme peroxidases also show a reasonable catalatic reactivity (Reaction 3) and use a second hydrogen peroxide molecule as two-electron donor, thereby releasing dioxygen. One additional activity catalysed by a special group of heme peroxidases is the peroxygenation reaction, i.e. the selective introduction of peroxide-derived oxygen functionalities into organic molecules (Reaction 4).

$${\text{H}}_{\text{2}}{\text{O}}_{\text{2}}+2{\text{AH}}_{\text{2}}\to {\text{H}}_{\text{2}}\text{O}+2{}^{•}\text{AH}$$Reaction 1

$${\text{H}}_{\text{2}}{\text{O}}_{\text{2}}+{\text{X}}^{-}+{\text{H}}^{+}\to {\text{H}}_{\text{2}}\text{O}+\text{HOX}$$Reaction 2

$${\text{H}}_{\text{2}}{\text{O}}_{\text{2}}+{\text{H}}_{\text{2}}{\text{O}}_{\text{2}}\to {\text{2H}}_{\text{2}}\text{O}+{\text{O}}_{\text{2}}$$Reaction 3

$${\text{H}}_{\text{2}}{\text{O}}_{\text{2}}+\text{RH}\to {\text{H}}_{\text{2}}\text{O}+\text{ROH}$$Reaction 4

In the last decade, an ever-increasing number of heme peroxidase sequences were automatically assigned to related families based on typical conserved motifs. It has been demonstrated that at least four heme peroxidase superfamilies arose independently during the evolution, which each differ in overall fold, active site architecture and enzymatic activities [1]: (i) the peroxidase-catalase superfamily [2,3], (ii) the peroxidase-cyclooxygenase superfamily [4], (iii) the peroxidase-peroxygenase superfamily [5,6] and (iv) the recently described dye-decolourizing peroxidases [7]. This review focuses on Families 1 and 2 of the peroxidase-cyclooxygenase superfamily [1,4,8].

Evolution and Functions of Peroxidases from the Peroxidase-Cyclooxygenase Superfamily

The peroxidase-cyclooxygenase superfamily has Pfam accession PF03098 (IPR019791), and its members are widely distributed among all domains of life [1,4]. It counts over 22,000 representatives in various sequence databases (June 2021) and shows the highest diversity regarding domain architectures and composition. The former denomination of these proteins as the “animal heme-dependent peroxidase family” is misleading but still present in some public databases. The superfamily comprises seven families, which – in contrast to the other heme peroxidase (super)families – are mostly multidomain proteins with one heme peroxidase domain of predominantly α-helical fold with a central heme-containing core of five α-helices. Moreover, this superfamily is unique in having the prosthetic heme group posttranslationally modified [9, 10, 11, 12 and 13]. The heme is covalently bound to the protein via one or two ester linkages formed by conserved Asp and Glu residues. In one representative (i.e. myeloperoxidase), a third heme to protein linkage is formed [14,15]. As a consequence of these modifications, the heme is electronically and structurally modified, and these peroxidases exhibit unique spectral, redox and catalytic properties [16, 17 and 18]. All representatives catalyse Reactions 1 and 2, but halide oxidation seems to be the dominating physiological enzymatic activity for most studied members.

The evolution of the peroxidase-cyclooxygenase superfamily starts with bacterial peroxicins (assigned previously as Family 5) [1]. From Family 5 via Family 6 (i.e. bacterial peroxidockerins), next evolutionary steps involved the formation of solely eukaryotic Family 3 (peroxinectins), Family 2 (peroxidasins) and, finally, Family 1 (chordata peroxidases), which includes thyroid peroxidase (TPO), lactoperoxidase (LPO), eosinophil peroxidase (EPO) and myeloperoxidase (MPO). The physiological roles of Families 5 and 6 peroxidases remain unknown. Peroxinectins (Family 3) were shown to exhibit cell adhesion functions and to be involved in invertebrate immune response by production of hypohalous acids according to Reaction 2 [19]. Peroxinectins are fusion proteins of a heme peroxidase domain with an integrin-binding motif that probably co-evolved from the ancestral dockerin part of peroxidockerins (Family 6) together with the peroxidase domain. Peroxinectins are widely distributed mainly among arthropods and nematodes where they are synthesized and stored in secretory granules in an inactive form, released in response to stimuli and activated outside the cells to mediate haemocyte attachment and spreading.

It has to be mentioned that an alternative evolutionary path led from Family 5 towards Family 4, which contains bacterial and animal cyclooxygenases as well as plant alpha dioxygenases, whereas animal dual oxidases (Family 7) already segregated from peroxidockerins at the level of basal eukaryotes that are still extant [1].

Family 2 (peroxidasins) and Family 1 (chordata peroxidases) represent the youngest addition in evolution of this superfamily. For this review, we perf...