DyP, a unique dye-decolorizing enzyme from the fungus Thanatephorus cucumeris Dec 1, has been classified as a peroxidase but lacks homology to almost all other known plant peroxidases. The primary structure of DyP shows moderate sequence homology to only two known proteins: the peroxidedependent phenol oxidase, TAP, and the hypothetical peroxidase, cpop21. Here, we show the first crystal structure of DyP and reveal that this protein has a unique tertiary structure with a distal heme region that differs from that of most other peroxidases. DyP lacks an important histidine residue known to assist in the formation of a Fe 4؉ oxoferryl center and a porphyrinbased cation radical intermediate (compound I) during the action of ubiquitous peroxidases. Instead, our tertiary structural and spectrophotometric analyses of DyP suggest that an aspartic acid and an arginine are involved in the formation of compound I. Sequence analysis reveals that the important aspartic acid and arginine mentioned above and histidine of the heme ligand are conserved among DyP, TAP, and cpop21, and structural and phylogenetic analyses confirmed that these three enzymes do not belong to any other families of peroxidase. These findings, which strongly suggest that DyP is a representative heme peroxidase from a novel family, should facilitate the identification of additional new family members and accelerate the classification of this novel peroxidase family.Peroxidases have been systematically researched for more than 70 years. Fifteen years ago, Welinder (1) proposed the concept of a "plant peroxidase superfamily" comprising classes I, II, and III, based on primary sequence alignments and isolation from prokaryotes, fungi, and plants, respectively. Using this strategy, yeast cytochrome c peroxidase (2) and chloroplast ascorbate peroxidase (3) were classified as class I peroxidases on account of their prokaryotic source. Representatives of class II include lignin peroxidase (LiP) 2 (4), manganese peroxidase (MnP) (5), and versatile peroxidase (6, 7), whereas class III contains horseradish peroxidase (HRP) (8) and barley grain peroxidase (BGP) (9). This classification has been widely applied to most known peroxidases, with the exception of chloroperoxidase (CPO) isolated from the fungus, Caldariomyces fumago, which lacks primary structural homology with other peroxidases (10, 11). However, in contrast to the plant peroxidases, those from animals, including mammals, are yet to be categorized. To date, most of these enzymes have been grouped into the plant or animal peroxidase superfamily (12).So far, we isolated and characterized a novel extracellular peroxidase, DyP, from the fungus Thanatephorus cucumeris Dec 1 (13-16). DyP, a glycoprotein having one heme as a cofactor, has a molecular mass of 58 kDa and requires H 2 O 2 for all enzyme reactions, indicating that it functions as a peroxidase. DyP has several characteristics that distinguish it from all other peroxidases, including a particularly wide substrate specificity, a lack of homology to m...
Dye-decolorizing peroxidase (DyP) is produced by a basidiomycete (Thanatephorus cucumeris Dec 1) and is a member of a novel heme peroxidase family (DyP-type peroxidase family) that appears to be distinct from general peroxidases. Thus far, 80 putative members of this family have been registered in the PeroxiBase database (http://peroxibase.isbsib.ch/) and more than 400 homologous proteins have been detected via PSI-BLAST search. Although few studies have characterized the function and structure of these proteins, they appear to be bifunctional enzymes with hydrolase or oxygenase, as well as typical peroxidase activities. DyP-type peroxidase family suggests an ancient root compared with other general peroxidases because of their widespread distribution in the living world. In this review, firstly, an outline of the characteristics of DyP from T. cucumeris is presented and then interesting characteristics of the DyP-type peroxidase family are discussed.
Mikio Ni~hizawa,~ Hepatic stellate cells (HSCs) spontaneously transdifferentiate into myofibroblast (MFB) -phenotype on plastic dishes. This response recapitulates the features of activation in viva Transforming growth &tor P (TGF-P) plays a prominent role in stimulating liver fibrogenesis by MFBs. In quiescent HSCs, TGF-P signaling involves TGF-P type I receptor (TPRI)-mediated phosphorylation of serine residues within the conserved SSXS motif at the C-terminus of Smad2 and Smad3. The middle linker regions of Smad2 and Smad3 also are phosphorylated by mitogenactivated protein b a s e (MAPK). This study elucidates the change of Smad3-mediated signals during the transdifferentiation process. By using antibodies highly specific to the phosphorylated C-terminal region and the phosphorylated linker region of Smad3, we found that TGF-& dependent Smad3 phosphorylation at the C-terminal region decreased, but that the phosphorylation at the linker region increased in the process of transdifferentiation. TGF-P activated the p38 MAPK pathway, further leading to Smad3 phosphorylation at the linker region in the cultured MFBs, irrespective of Smad2. The phosphorylation promoted hetero-complex formation and nuclear translocation of Smad3 and Smad4. Once combined with TPRI-phosphorylated Smad2, the Smad3 and Smad4 complex bound to plasminogen activator inhibitor-type I promoter could enhance the transcription. In addition, Smad3 phosphorylation mediated by the activated TPRI was impaired severely in MFBs during chronic liver injury, whereas Smad3 phosphorylation at the linker region was remarkably induced by p38 MAPK pathway. In conclusion, p38 MAPK-dependent Smad3 phosphorylation promoted extracellular matrix production in MFBs both in vitro and in viva (HEPATOLOGY 2003 age as well as after their prolonged culture on plastic dishes.' This process involves changes in the cell morphology and gene expression and is characterized by the gradual loss in the retinoid content and the synthesis of a large amount of extracellular matrix (ECM) components.Transforming growth factor P (TGF-P) is an important mediator of ECM accumulation and is involved in a variety of physiologic and pathologic processes.2 In particular, the expression of TGF-/3 at high steady-state levels associated with the accelerated ECM accumulation in MFBs is a common finding in human chronic liver disease of different etiologies.3 Uncontrolled ECM accumulation mediated by TGF-P is thought to be essential for the development of liver fibrosis. However, the change of TGF-P signals during the transdifferentiation process of HSCs remains unclear.O n the other hand, recent studies over the past several years have elucidated how TGF-P initiates its response. TGF-/3 transduces the signal from its receptor to nucleus through Smads.4 The activated TGF-P type I receptor (TPRI) phosphorylates such receptor-regulated Smads 879
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