The peroxidase–cyclooxygenase superfamily: Reconstructed evolution of critical enzymes of the innate immune system

Abstract

The authors have reconstructed the phylogenetic relationships of the main evolutionary lines of mammalian heme containing peroxidases. The sequences of intensively investigated human myeloperoxidase, eosinophil peroxidase, and lactoperoxidase, which participate in host defence against infections, were aligned together with newly found open reading frames coding for highly similar putative peroxidase domains in all kingdoms of life. The evolutionary relationships were reconstructed using neighbor-joining, maximum parsimony, and maximum likelihood methods. It is demonstrated that this enzyme superfamily obeys the rules of birth-and-death model of multigene family evolution and contains proteins with a variety of function that could be grouped in seven subfamilies. On the basis of occurrence and the fact that two main enzymatic activities are related with these metalloproteins, they propose the name peroxidase-cyclooxygenase superfamily for this widely spread group of heme-containing oxidoreductases. Well known structure-function relationships in mammalian peroxidases formed the basis for the critical inspection of all subfamilies. The presented data unequivocally suggest that predecessor genes of mammalian heme peroxidases have segregated very early in evolution. Before organisms developed an acquired immunity, their antimicrobial defence depended on enzymes that were recruited upon pathogen invasion and could produce antimicrobial reaction products. Thus, these peroxidatic heme proteins evolved to important components in the innate immune defence system. This work shows that even in certain prokaryotic organisms, genes encoding putative antimicrobial enzymes are found providing a group of bacteria with an evolutionary advantage over the others.

Proprotein Convertase Processing Enhances Peroxidasin Activity to Reinforce Collagen IV

“…Based on this and prior work, a model for Pxdn biosynthesis may be proposed. Pxdn monomers may initially trimerize through the vWFC domain, which allows for cysteines throughout the remainder of the molecule to approach one another and form disulfide linkages to covalently consolidate the homotrimeric state (7,13,16) C.…”

“…Peroxidasin is a member of the animal heme peroxidase superfamily along with myeloperoxidase (MPO), eosinophil peroxidase, lactoperoxidase, and thyroid peroxidase (TPO) (7,8). Peroxidases use hydrogen peroxide (H 2 O 2 ) to oxidize halide ions (X Ϫ ϭ I Ϫ , Br Ϫ , Cl Ϫ ) and form hypohalous acids (HOX).…”

“…Given its critical function in the synthesis of basement membranes, it is no surprise that peroxidasin is found throughout the animal kingdom, whereas other animal heme peroxidases are restricted to vertebrates (10,11). In addition, unlike other members of the animal heme peroxidase family, Pxdn is a multidomain protein that contains a leucine-rich region followed by four immunoglobulin-like domains, the catalytic peroxidase domain, and a C terminal von Willebrand factor type C (vWFC) domain (7,12,13). The non-catalytic domains are generally thought to participate in protein-protein interactions.…”

A Stable Bacterial Peroxidase with Novel Halogenating Activity and an Autocatalytically Linked Heme Prosthetic Group

“…Reconstruction of the phylogeny of the peroxidase-cyclooxygenase superfamily revealed the occurrence of seven subfamilies (2). Subfamily 1 is already well investigated and composed of vertebrate peroxidases, including myeloperoxidase (MPO), 2 eosinophil peroxidase (EPO), lactoperoxidase (LPO), and thyroid peroxidase (TPO).…”

“…Subfamily 1 is already well investigated and composed of vertebrate peroxidases, including myeloperoxidase (MPO), 2 eosinophil peroxidase (EPO), lactoperoxidase (LPO), and thyroid peroxidase (TPO). The main catalytic activity of these oxidoreductases is the two-electron oxidation of halides or thiocyanate mediated by hydrogen peroxide.…”