Myeloperoxidase structure

Blair-Johnson M, Eiedler T, Eenna R. Human myeloperoxidase structure of a cyanide complex and its interaction with bromide and thiocyanate substrates at 1.9 A resolution. Biochemistry 2001 40 13990-13997. 

L.B. Dugad, G.N. LaMar, H.C. Lee, M. Ikeda-Saito, K.S. Booth, and W.S. Caughey, A nuclear Overhauser effect study of the active site of myeloperoxidase. Structural similarity of the prosthetic group to that on lactoperoxidase, J. Biol. Chem. 265 71173 (1990). 

Histochemical studies of bone marrow samples show that peroxidase-containing granules are detectable in promyelocytes. The human promyelo-cytic leukaemia cell line HL-60 grows easily in culture, and the cells resemble promyelocytes both structurally and functionally. Furthermore, they can be induced to differentiate in vitro upon addition of various agents, such as retinoic acid and phorbol esters, and these differentiated cells resemble more mature forms of neutrophils. HL-60 cells possess almost the same amount of myeloperoxidase (4.4 fig per 106 cells) as mature neutrophils, and the enzyme purified from these cells has the same subunit structure. The cells thus actively synthesise the enzyme only until they are induced to differentiate. This cell line has been extensively used to study the molecular events controlling the expression of enzymes such as myeloperoxidase, and also to investigate the molecular controls that lead to a cessation of their expression. 

Fiedler TJ, Davey CA, Fenna RE (2000) X-Ray Crystal Structure and Characterization of Halide-Binding Sties of Human Myeloperoxidase at 1.8 A Resolution. J Biol Chem 275 11964... 

Zeng J, Fenna RE (1992) X-ray crystal-structure of canine myeloperoxidase at 3 A resolution. J Mol Biol 226 185-207... 

Several of the proteins with ferryl intermediates have been crystalised at sufficient resolution to allow the elucidation of their 3-dimensional structure. These include cytochrome c peroxidase [95], horseradish peroxidase [96], catalase [97], myeloperoxidase [98], ribonucleotide reductase [99], cytochrome P-450 [100] and myoglobin [101]. Of these only cytochrome c peroxidase has proved stable enough to crystallise with the iron in the ferryl form [26]. High-resolution structures exist for small FeIV model compounds, both in the presence [102] and absence [7,8] of an Fe=0 bond. These compounds can have sulphur, nitrogen and chloride ligation to the iron and the iron can be five [7,8] or six [8] coordinate. 

H8. Harrison, J. E., Pabalan, S., and Schultz, J., The subunit structure of crystalline canine myeloperoxidase. Biochim. Biophys. Acta 493,247—259 (1977). 

Crystallography revealed a bound chloride ion at the amino terminus of the helix containing the proximal His336 which can be replaced with bromide. Crystal structures of the human MPO-cyanide, MPO-cyanide-bromide, and MPO-cyanide-thiocyanate have also been determined by Fenna and coworkers to 1.9 A. These results support a model for a single common binding site for halides and thiocyanate as substrates or as inhibitors near the S-meso carbon of the porphyrin ring in myeloperoxidase. 

Under apoptotic conditions in human cells, TyrRS is secreted and then cleaved by the extracellular enzyme leukocyte elas-tase into two fragments. The two fragments have distinct cytokine activities (23). The C-terminal fragment is homologous to the endothelial monocyte-activating polypeptide-II cytokine. It stimulates the production of myeloperoxidase, TNF-a, tissue factor, and migration of polymorphonuclear and human umbilical vein endothelial cells. It also has leukocyte and monocyte chemotaxis activities, which are dependent on a heptapeptide located in the first fi-strand of the fS-barrel structure. 

Fig, 8. Active-site structure of canine myeloperoxidase. The dashed line shows the H-bond between N1 of the proximal His336 and the side-chain carbonyl of Asn421. This diagram was generated using the X-ray coordinates for the 3-A structure of MPO (7). 

Figure 9 Structure of myeloperoxidase (MPO) along with the heme environment as observed in the high-resoiution crystal stmcture. (This figure was generated from coordinates of ICXP deposited in the Protein Data Banlr)...

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