• Prosthetic group features
• Animal haem peroxidases in enzyme databases
• Animal haem peroxidases in motif databases
• Animal haem peroxidases in alignment databases
• Animal haem peroxidases in 3­D databases
• References

Haem type	Haem iron coordination	Axial iron ligand(s)	Formal iron oxidation/spin states
Haem b	Pentacoordinate / Hexacoordinate	NHis; (H2O or OH¯)	FeII (S=2); FeIII (S=5/2)
	Hexacoordinate	NHis; H2O, H2O2 or O2	FeII (S=0); FeIII (S=1/2)
	Hexacoordinate	NHis; O (O·)	FeIV (S=1)

Peroxidases are haem­containing enzymes that use hydrogen peroxide (H₂O₂) as the electron acceptor to catalyse a number of oxidative reactions [1]. Peroxidases are found in bacteria, fungi, plants and animals. On the basis of sequence similarity, a number of animal haem peroxidases can be categorised as members of a superfamily: myeloperoxidase (MPO); eosinophil peroxidase (EPO); lactoperoxidase (LPO); thyroid peroxidase (TPO); prostaglandin H synthase (PGHS); and peroxidasin [2-4].

To date, the 3­D structures of MPO and PGHS have been reported. MPO is a homodimer: each monomer consists of a light (A or B) and a heavy (C or D) chain resulting from post­translational excision of six residues from the common precursor. Monomers are linked by a single inter­chain disulphide (see Figure 1MHL a). Each monomer includes a bound calcium ion [5]. PGHS exists as a symmetric dimer, each monomer of which consists of three domains: an N­terminal epidermal growth factor (EGF) like module; a membrane­binding domain; and a large C­terminal catalytic domain containing the cyclooxygenase and peroxidase active sites. The catalytic domain shows striking structural similarity to MPO. The cyclooxygenase active site, which catalyses the formation of prostaglandin G₂ (PGG2) from arachidonic acid, resides at the apex of a long hydrophobic channel, extending from the membrane­binding domain to the centre of the molecule. The peroxidase active site, which catalyses the reduction of PGG2 to PGH2, is located on the other side of the molecule, at the haem binding site [6]. Both MPO and the catalytic domain of PGHS are mainly ­helical (see Figure 1MHL b), 19 helices being identified as topologically and spatially equivalent; PGHS contains five additional N­terminal helices that have no equivalent in MPO. In both proteins, three Asn residues in each monomer are glycosylated.

A refined X­ray structure of human myeloperoxidase has shown that the haem is a novel derivative of protoporphyrin IX in which three ring substituents form covalent bonds with amino acid side chains in the protein [7]. Modified methyl groups on pyrrole rings A and C form ether linkages with Glu­242 and Asp­94, respectively, while a covalent bond between the vinyl group on ring A and the sulphur atom of Met­243 results in a sulphonium ion linkage:

Figure 1MHL c shows the structure of myeloperoxidase active site. The imidazole ring of proximal His­336 lies approximately perpendicular to the porphyrin plane with N² bonded to haem iron and N¹ hydrogen bonded to the buried carboxylate group of Asp­421. On the distal side of the haem, His­95 and Arg­239 are likely to form a ligand pocket for H₂O₂, in a manner analogous to the distal His and Arg of the non­homologous enzyme cytochrome c peroxidase (cf. Figure 2CYP).

Animal haem peroxidases in enzyme databases

Note: Peroxidase (EC 1.11.1.7) includes both animal and fungal, plant and bacterial haem peroxidases.

Animal haem peroxidases in motif databases

PRINTS ID	PRINTS AC	PROSITE/BLOCKS ID	PROSITE AC	BLOCKS AC
ANPEROXIDASE	PR00457	PEROXIDASE_1 PEROXIDASE_2	PS00435 PS00436	BL00435

Animal haem peroxidases in alignment databases

Protein (Super)Family	Protein Homology Domain	Pfam	LPFC 3­D alignment
00171; myeloperoxidase 03929; thyroid peroxidase 06602; cyclooxygenase	00351; myeloperoxidase	-	-

PDB	scop	BSM	RELI Base	Header	¹
1cx2	-	1cx2	-	Cyclooxygenase­2 (complex with selective inhibitor SC­558) (modified with N­acetyl­D­glucosamine); mouse	MS7RRC22
1mhl	1mhl	1mhl	1mhl	Myeloperoxidase (complex with Ca2+ and Cl¯) (modified with N­acetyl­D­glucosamine, ­D­mannose and fucose); human	-
1myp	1myp	1myp	1myp	Myeloperoxidase (complex with Ca2+) (modified with N­acetyl­D­glucosamine); dog	MMS93137
1pge	1pge	1pge	1pge	Prostaglandin H2 synthase­1 [complex with p­(2'­iodo­5'­thenoyl)hydrotropic acid] (modified with N­acetyl­D­glucosamine and B­octylglucoside); sheep seminal vesicles	-
1pgf	1pgf	1pgf	1pgf	Prostaglandin H2 synthase­1 [complex with 1­(4­iodobenzoyl)­5­methoxy­2­methylindole­3­acetic acid, cis model] (modified with N­acetyl­D­glucosamine); sheep seminal vesicles	-
1pgg	1pgg	1pgg	1pgg	Prostaglandin H2 synthase­1 [complex with 1­(4­iodobenzoyl)­5­methoxy­2­methylindole­3­acetic acid, trans model] (modified with N­acetyl­D­glucosamine); sheep seminal vesicles	-
1prh	1prh	1prh	1prh	Prostaglandin H2 synthase­1; sheep seminal vesicles	MS5TL1
1pth	1pth	1pth	1pth	Prostaglandin H2 synthase­1 (complex with salicylic acid and B­octylglucoside) (modified with N­acetyl­D­glucosamine; the side chain oxygen of Ser­530 is etherified with a 2­bromoacetyl group); sheep seminal vesicles	-
3pgh	-	3pgh	-	Cyclooxygenase­2 (complex with non­selective inhibitor flurbiprofen) (modified with N­acetyl­D­glucosamine); mouse	MS7RR5
4cox	-	4cox	-	Cyclooxygenase­2 (complex with non­selective inhibitor indomethacin) (modified with N­acetyl­D­glucosamine); human	MS7MMC20
5cox	-	5cox	-	Cyclooxygenase­2; mouse	MS7RR5
6cox	-	6cox	-	Cyclooxygenase­2 (complex with selective inhibitor SC­558 in I222 space group) (modified with N­acetyl­D­glucosamine); mouse	MS7RRC22

¹ Macromolecular Structures abstract. Full text is available to BioMedNet Members

References

1. Everse, J., Everse, K.E. and Grisham, M.B., Eds. (1991) Peroxidases in Chemistry and Biology. CRC Press, Boca Raton.
2. Kimura, S. and Ikeda­Saito, M. (1988) Human myeloperoxidase and thyroid peroxidase, two enzymes with separate and distinct physiological functions, are evolutionarily related members of the same gene family. Proteins 3, 113-120.
3. Marnett, I. (1990) Prostaglandin H synthase. In Reddy, C.C., Hamilton, G.A. and Madyastha, K.N., Eds. Biological oxidation systems. Academic Press, San Diego, Vol.2, pp.637-655.
4. Nelson, R.E., Fessler, L.I., Takagi, Y., Blumberg, B., Keene, D.R., Olson, P.F., Parker, C.G. and Fessler, J.H. (1994) Peroxidasin: a novel enzyme-matrix protein of Drosophila development. EMBO J. 13, 3438-3447.
5. Zeng, J. and Fenna, R.E. (1992) X­ray crystal structure of canine myeloperoxidase at 3 Å resolution. J. Mol. Biol. 226, 185-207.
6. Picot, D., Loll, P.J. and Garavito, R.M. (1994) The X­ray crystal structure of the membrane protein prostaglandin H₂ synthase­1. Nature 367, 243-249.
7. Fenna, R.E., Zeng, J. and Davey, C. (1995) Structure of the green heme in myeloperoxidase. Arch. Biochem. Biophys. 316, 653-656.

Bibliography on structural studies of animal haem peroxidases

Reviews on animal haem peroxidases