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• W1973074311 abstract "Trametes villosa laccase was mutated on a tetrapeptide segment near the type 1 site. The mutations F463M and F463L were at the position corresponding to the type 1 copper axial methionine (M517) ligand in Zucchini ascorbate oxidase. The mutations E460S and A461E were near the T1 copper site. The mutatedTrametes laccases were expressed in an Aspergillus oryzae host and characterized. The E460S mutation failed to produce a transformant with meaningful expression. The F463L and A461E mutations did not significantly alter the molecular and enzymological properties of the laccase. In contrast, the F463M mutation resulted in a type 1 copper site with an EPR signal intermediate between that of the wild type laccase and plastocyanin, an altered UV-visible spectrum, and a decreased redox potential (by 0.1 V). In oxidizing phenolic substrate, the mutation led to a more basic optimal pH as well as an increase in k cat and K m. These effects are attributed to a significant perturbation of the T1 copper center caused by the coordination of the axial methionine (M463) ligand. Trametes villosa laccase was mutated on a tetrapeptide segment near the type 1 site. The mutations F463M and F463L were at the position corresponding to the type 1 copper axial methionine (M517) ligand in Zucchini ascorbate oxidase. The mutations E460S and A461E were near the T1 copper site. The mutatedTrametes laccases were expressed in an Aspergillus oryzae host and characterized. The E460S mutation failed to produce a transformant with meaningful expression. The F463L and A461E mutations did not significantly alter the molecular and enzymological properties of the laccase. In contrast, the F463M mutation resulted in a type 1 copper site with an EPR signal intermediate between that of the wild type laccase and plastocyanin, an altered UV-visible spectrum, and a decreased redox potential (by 0.1 V). In oxidizing phenolic substrate, the mutation led to a more basic optimal pH as well as an increase in k cat and K m. These effects are attributed to a significant perturbation of the T1 copper center caused by the coordination of the axial methionine (M463) ligand. Laccase (p-diphenol:dioxygen oxidoreductase, EC1.10.3.2) is a copper-containing oxidase that couples the oxidation of substrate (usually diphenols, aryl diamines, or amino phenols) with the reduction of dioxygen to water (1Mayer A.M. Phytochemistry. 1987; 26: 11-20Crossref Scopus (703) Google Scholar, 2Messerschmidt A. Huber R. Eur. J. Biochem. 1990; 187: 341-352Crossref PubMed Scopus (386) Google Scholar, 3Solomon E.I. Machonkin T.E. Sundaram U.M. Messerschmidt A. Multi-Copper Oxidases. World Scientific, Singapore1997: 103-128Crossref Google Scholar, 4$$Google Scholar). Sequence comparisons, crystal structure analyses, and spectroscopy indicate that all multicopper oxidases contain at least one type 1 (T1) 1The abbreviations used are: T1, type 1 copper; T2, type 2 copper; T3, type 3 copper; TvL, recombinant T. villosa (Polyporus pinsitus) laccase (isozyme 1); RsL, recombinantR. solani laccase; MtL, recombinant M. thermophila laccase; CcL, recombinant C. cinereuslaccase; PvL, T. (Polyporus) versicolor laccase; zAO, Zucchini ascorbate oxidase; RvL, R. verniciferalaccase; Pc, poplar plastocyanin; wt, wild type; ABTS, 2,2′-azinobis-(3-ethylbenzothiazoline-6-sulfonic acid); SGZ, syringaldazine; E°, single-electron redox potential (referenced to the normal hydrogen electrode) at T1 site; pHopt, optimal pH; G, gauss; MES, 4-morpholineethanesulfonic acid.1The abbreviations used are: T1, type 1 copper; T2, type 2 copper; T3, type 3 copper; TvL, recombinant T. villosa (Polyporus pinsitus) laccase (isozyme 1); RsL, recombinantR. solani laccase; MtL, recombinant M. thermophila laccase; CcL, recombinant C. cinereuslaccase; PvL, T. (Polyporus) versicolor laccase; zAO, Zucchini ascorbate oxidase; RvL, R. verniciferalaccase; Pc, poplar plastocyanin; wt, wild type; ABTS, 2,2′-azinobis-(3-ethylbenzothiazoline-6-sulfonic acid); SGZ, syringaldazine; E°, single-electron redox potential (referenced to the normal hydrogen electrode) at T1 site; pHopt, optimal pH; G, gauss; MES, 4-morpholineethanesulfonic acid.copper center, one type 2 (T2) copper center, and one type 3 (T3) copper center (3Solomon E.I. Machonkin T.E. Sundaram U.M. Messerschmidt A. Multi-Copper Oxidases. World Scientific, Singapore1997: 103-128Crossref Google Scholar, 4$$Google Scholar, 5Messerschmidt A. Ladenstein R. Huber R. Bolognesi M. Avigliano L. Petruzzelli R. Rossi A. Finazzi-Agro A. J. Mol. Biol. 1992; 224: 179-205Crossref PubMed Scopus (440) Google Scholar, 6Zaitseva I. Zaitsev V. Card G. Moshkov K. Bax B. Ralph A. Lindley P. J. Bioinorg. Chem. 1996; 1: 15-23Google Scholar, 7Ducros V. Brzozowski A.M. Wilson K.S. Brown S.H. Østergaard P. Schneider P. Yaver D.S. Pedersen A.H. Davies G.J. Nat. Struct. Biol. 1998; 5: 310-316Crossref PubMed Scopus (346) Google Scholar). These copper sites are defined by their spectroscopic properties. The T1, or “blue,” copper is characterized by an intense (ε ∼ 5000m−1 cm−1) absorption band around 600 nm and an unusually small (<100 × 10−4cm−1) parallel hyperfine coupling in EPR. The T2, or normal, copper site does not exhibit a strong feature in the visible absorption spectrum, but has a parallel hyperfine coupling > 160 × 10−4 cm−1. The T3, or coupled binuclear, copper center consists of two copper atoms connected by a hydroxide bridge. This bridge provides a strong superexchange pathway and therefore mediates antiferromagnetic coupling. The T3 center is EPR-silent, but is characterized by an absorption band around 330 nm (ε ∼ 5000 m−1 cm−1). The T2 and T3 sites form a trinuclear copper cluster that is the site for O2 reduction (5Messerschmidt A. Ladenstein R. Huber R. Bolognesi M. Avigliano L. Petruzzelli R. Rossi A. Finazzi-Agro A. J. Mol. Biol. 1992; 224: 179-205Crossref PubMed Scopus (440) Google Scholar, 8Spira-Solomon D.J. Allendorf M.D. Solomon E.I. J. Am. Chem. Soc. 1986; 108: 1533-1538Crossref Scopus (151) Google Scholar, 9Cole J.L. Tan G.O. Yang E.K. Hodgson K.O. Solomon E.I. J. Am. Chem. Soc. 1990; 112: 2243-2249Crossref Scopus (89) Google Scholar). Laccase is the simplest of the multicopper oxidases, containing one of each type of copper site for a total of 4 copper atoms.Based on a wide range of comparative studies, including sequence homology and crystal structure analysis, the copper site coordination is very similar among the multicopper oxidases. The main difference is in the coordination sphere of the T1 copper site. The typical T1 site, such as that found in the blue copper protein plastocyanin (Pc) and the multi-copper protein Zucchini ascorbate oxidase (zAO), contains two histidines (His), a cysteine (Cys) that forms a short S-Cu bond, and a methionine (Met) that forms a long S-Cu bond. These four ligands bind T1 copper in a distorted tetrahedral coordination geometry (Fig. 1, A and B). In contrast, most fungal laccases with known primary sequence have either a leucine (Leu) or phenylalanine (Phe) at the position corresponding to the axial Met ligand (3Solomon E.I. Machonkin T.E. Sundaram U.M. Messerschmidt A. Multi-Copper Oxidases. World Scientific, Singapore1997: 103-128Crossref Google Scholar, 5Messerschmidt A. Ladenstein R. Huber R. Bolognesi M. Avigliano L. Petruzzelli R. Rossi A. Finazzi-Agro A. J. Mol. Biol. 1992; 224: 179-205Crossref PubMed Scopus (440) Google Scholar). Neither Leu nor Phe would be expected to coordinate to the copper that would render a tri-coordinate T1 site. The recent crystal structure of Coprinus cinereus laccase (CcL) confirms this and shows that the T1 site has only three ligands (two His and one Cys) in a trigonal planar geometry (Fig.1 C) (7Ducros V. Brzozowski A.M. Wilson K.S. Brown S.H. Østergaard P. Schneider P. Yaver D.S. Pedersen A.H. Davies G.J. Nat. Struct. Biol. 1998; 5: 310-316Crossref PubMed Scopus (346) Google Scholar). An interesting question is how this difference in geometry is manifested in terms of differences in the electronic structure and the electron transfer function of the T1 site. The redox potential (E°) of fungal laccases ranges from 0.48 V to 0.78 V, whereas Pc and zAO haveE° in the range of 0.3 to 0.4 V (3Solomon E.I. Machonkin T.E. Sundaram U.M. Messerschmidt A. Multi-Copper Oxidases. World Scientific, Singapore1997: 103-128Crossref Google Scholar). It has been proposed that the lack of an axial ligand might be responsible for the highE° observed in some fungal laccases (10Gray H.B. Malmström B.G. Commun. Inorg. Chem. 1983; 2: 203-209Crossref Scopus (156) Google Scholar, 11Guckert J.A. Lowery M.D. Solomon E.I. J. Am. Chem. Soc. 1995; 117: 2814-2844Crossref Scopus (193) Google Scholar, 12Eggert C. Lafayette P.R. Temp U. Eriksson K.-E.L. Dean J.F.D. Appl. Environ. Microbiol. 1998; 64: 1766-1772Crossref PubMed Google Scholar), as it is expected that the elimination of the axial Met donor interaction would preferentially stabilize the reduced Cu(I) state. A number of mutagenesis studies (13Karlsson B.G. Aasa R. Malmström B.G. Lundberg L.G. FEBS Lett. 1989; 253: 99-102Crossref Scopus (74) Google Scholar, 14Pascher T. Karlsson B.G. Nordling M. Malmström B.G. Vanngard T. Eur. J. Biochem. 1993; 212: 289-296Crossref PubMed Scopus (149) Google Scholar, 15Romero A. Hoitink C.W.G. Nar H. Huber R. Messerschmidt A. Canters G.W. J. Mol. Biol. 1993; 229: 1007-1021Crossref PubMed Scopus (165) Google Scholar) have been performed on the T1 copper site in azurin, and it was found that the nature of the axial ligand can influence E° to some extent. Mutation of Met-121 was found to tune the E° over a range of −0.105 V to 0.138 V with respect to the E° of the wild-type (wt) azurin at pH 7.0.The present study utilized site-directed mutagenesis to examine how the composition of the amino acid residues in the vicinity of the T1 copper affect the structure and E° of this copper in aTrametes villosa laccase (TvL) (16Yaver D.S. Xu F. Golightly E.J. Brown K.M. Brown S.H. Rey M.W. Schneider P. Halkier T. Mondorf K. Dalbøge H. Appl. Environ. Microbiol. 1996; 62: 834-841Crossref PubMed Google Scholar). We were also interested in determining how the mutations would impact the enzymatic properties,k cat, K m, and the pH dependence of enzymatic activity. TvL has a primary structure and redox/enzymatic properties very similar to the Trametes (Polyporus or Coriolus) versicolor laccase (PvL), an enzyme that has been extensively studied and is regarded as a representative high E° laccase (1Mayer A.M. Phytochemistry. 1987; 26: 11-20Crossref Scopus (703) Google Scholar, 2Messerschmidt A. Huber R. Eur. J. Biochem. 1990; 187: 341-352Crossref PubMed Scopus (386) Google Scholar, 3Solomon E.I. Machonkin T.E. Sundaram U.M. Messerschmidt A. Multi-Copper Oxidases. World Scientific, Singapore1997: 103-128Crossref Google Scholar, 4$$Google Scholar). We mutated Phe-463, which corresponds to the axial Met-517 in zAO, and two other residues (Glu-460 and Ala-461), corresponding to the His-514 and Met-515 in zAO (Table I). Our results showed that the F463M mutation led to significant changes in the T1 copper site, decreased the E°, and altered k catand K m.Table ISequence alignment between zAO, TvL, and CcLLaccaseSequence alignmentE°VTvL452HCHIDFHLEAGF4630.78PvL451HCHIDFHLEAGF4620.79RsL459HCHIDWHLEAGL4700.71MtL502HCHIAWHVSGGL5130.47CcL451HCHIEFHLMNGL4620.55zAO506HCHIEPHLHMGM5170.34*‡* ‡ ‡Underlined letters represent the mutated residues of this study. *, ligand to T3 copper; ‡, ligand to T1 copper. Open table in a new tab Laccase (p-diphenol:dioxygen oxidoreductase, EC1.10.3.2) is a copper-containing oxidase that couples the oxidation of substrate (usually diphenols, aryl diamines, or amino phenols) with the reduction of dioxygen to water (1Mayer A.M. Phytochemistry. 1987; 26: 11-20Crossref Scopus (703) Google Scholar, 2Messerschmidt A. Huber R. Eur. J. Biochem. 1990; 187: 341-352Crossref PubMed Scopus (386) Google Scholar, 3Solomon E.I. Machonkin T.E. Sundaram U.M. Messerschmidt A. Multi-Copper Oxidases. World Scientific, Singapore1997: 103-128Crossref Google Scholar, 4$$Google Scholar). Sequence comparisons, crystal structure analyses, and spectroscopy indicate that all multicopper oxidases contain at least one type 1 (T1) 1The abbreviations used are: T1, type 1 copper; T2, type 2 copper; T3, type 3 copper; TvL, recombinant T. villosa (Polyporus pinsitus) laccase (isozyme 1); RsL, recombinantR. solani laccase; MtL, recombinant M. thermophila laccase; CcL, recombinant C. cinereuslaccase; PvL, T. (Polyporus) versicolor laccase; zAO, Zucchini ascorbate oxidase; RvL, R. verniciferalaccase; Pc, poplar plastocyanin; wt, wild type; ABTS, 2,2′-azinobis-(3-ethylbenzothiazoline-6-sulfonic acid); SGZ, syringaldazine; E°, single-electron redox potential (referenced to the normal hydrogen electrode) at T1 site; pHopt, optimal pH; G, gauss; MES, 4-morpholineethanesulfonic acid.1The abbreviations used are: T1, type 1 copper; T2, type 2 copper; T3, type 3 copper; TvL, recombinant T. villosa (Polyporus pinsitus) laccase (isozyme 1); RsL, recombinantR. solani laccase; MtL, recombinant M. thermophila laccase; CcL, recombinant C. cinereuslaccase; PvL, T. (Polyporus) versicolor laccase; zAO, Zucchini ascorbate oxidase; RvL, R. verniciferalaccase; Pc, poplar plastocyanin; wt, wild type; ABTS, 2,2′-azinobis-(3-ethylbenzothiazoline-6-sulfonic acid); SGZ, syringaldazine; E°, single-electron redox potential (referenced to the normal hydrogen electrode) at T1 site; pHopt, optimal pH; G, gauss; MES, 4-morpholineethanesulfonic acid.copper center, one type 2 (T2) copper center, and one type 3 (T3) copper center (3Solomon E.I. Machonkin T.E. Sundaram U.M. Messerschmidt A. Multi-Copper Oxidases. World Scientific, Singapore1997: 103-128Crossref Google Scholar, 4$$Google Scholar, 5Messerschmidt A. Ladenstein R. Huber R. Bolognesi M. Avigliano L. Petruzzelli R. Rossi A. Finazzi-Agro A. J. Mol. Biol. 1992; 224: 179-205Crossref PubMed Scopus (440) Google Scholar, 6Zaitseva I. Zaitsev V. Card G. Moshkov K. Bax B. Ralph A. Lindley P. J. Bioinorg. Chem. 1996; 1: 15-23Google Scholar, 7Ducros V. Brzozowski A.M. Wilson K.S. Brown S.H. Østergaard P. Schneider P. Yaver D.S. Pedersen A.H. Davies G.J. Nat. Struct. Biol. 1998; 5: 310-316Crossref PubMed Scopus (346) Google Scholar). These copper sites are defined by their spectroscopic properties. The T1, or “blue,” copper is characterized by an intense (ε ∼ 5000m−1 cm−1) absorption band around 600 nm and an unusually small (<100 × 10−4cm−1) parallel hyperfine coupling in EPR. The T2, or normal, copper site does not exhibit a strong feature in the visible absorption spectrum, but has a parallel hyperfine coupling > 160 × 10−4 cm−1. The T3, or coupled binuclear, copper center consists of two copper atoms connected by a hydroxide bridge. This bridge provides a strong superexchange pathway and therefore mediates antiferromagnetic coupling. The T3 center is EPR-silent, but is characterized by an absorption band around 330 nm (ε ∼ 5000 m−1 cm−1). The T2 and T3 sites form a trinuclear copper cluster that is the site for O2 reduction (5Messerschmidt A. Ladenstein R. Huber R. Bolognesi M. Avigliano L. Petruzzelli R. Rossi A. Finazzi-Agro A. J. Mol. Biol. 1992; 224: 179-205Crossref PubMed Scopus (440) Google Scholar, 8Spira-Solomon D.J. Allendorf M.D. Solomon E.I. J. Am. Chem. Soc. 1986; 108: 1533-1538Crossref Scopus (151) Google Scholar, 9Cole J.L. Tan G.O. Yang E.K. Hodgson K.O. Solomon E.I. J. Am. Chem. Soc. 1990; 112: 2243-2249Crossref Scopus (89) Google Scholar). Laccase is the simplest of the multicopper oxidases, containing one of each type of copper site for a total of 4 copper atoms. Based on a wide range of comparative studies, including sequence homology and crystal structure analysis, the copper site coordination is very similar among the multicopper oxidases. The main difference is in the coordination sphere of the T1 copper site. The typical T1 site, such as that found in the blue copper protein plastocyanin (Pc) and the multi-copper protein Zucchini ascorbate oxidase (zAO), contains two histidines (His), a cysteine (Cys) that forms a short S-Cu bond, and a methionine (Met) that forms a long S-Cu bond. These four ligands bind T1 copper in a distorted tetrahedral coordination geometry (Fig. 1, A and B). In contrast, most fungal laccases with known primary sequence have either a leucine (Leu) or phenylalanine (Phe) at the position corresponding to the axial Met ligand (3Solomon E.I. Machonkin T.E. Sundaram U.M. Messerschmidt A. Multi-Copper Oxidases. World Scientific, Singapore1997: 103-128Crossref Google Scholar, 5Messerschmidt A. Ladenstein R. Huber R. Bolognesi M. Avigliano L. Petruzzelli R. Rossi A. Finazzi-Agro A. J. Mol. Biol. 1992; 224: 179-205Crossref PubMed Scopus (440) Google Scholar). Neither Leu nor Phe would be expected to coordinate to the copper that would render a tri-coordinate T1 site. The recent crystal structure of Coprinus cinereus laccase (CcL) confirms this and shows that the T1 site has only three ligands (two His and one Cys) in a trigonal planar geometry (Fig.1 C) (7Ducros V. Brzozowski A.M. Wilson K.S. Brown S.H. Østergaard P. Schneider P. Yaver D.S. Pedersen A.H. Davies G.J. Nat. Struct. Biol. 1998; 5: 310-316Crossref PubMed Scopus (346) Google Scholar). An interesting question is how this difference in geometry is manifested in terms of differences in the electronic structure and the electron transfer function of the T1 site. The redox potential (E°) of fungal laccases ranges from 0.48 V to 0.78 V, whereas Pc and zAO haveE° in the range of 0.3 to 0.4 V (3Solomon E.I. Machonkin T.E. Sundaram U.M. Messerschmidt A. Multi-Copper Oxidases. World Scientific, Singapore1997: 103-128Crossref Google Scholar). It has been proposed that the lack of an axial ligand might be responsible for the highE° observed in some fungal laccases (10Gray H.B. Malmström B.G. Commun. Inorg. Chem. 1983; 2: 203-209Crossref Scopus (156) Google Scholar, 11Guckert J.A. Lowery M.D. Solomon E.I. J. Am. Chem. Soc. 1995; 117: 2814-2844Crossref Scopus (193) Google Scholar, 12Eggert C. Lafayette P.R. Temp U. Eriksson K.-E.L. Dean J.F.D. Appl. Environ. Microbiol. 1998; 64: 1766-1772Crossref PubMed Google Scholar), as it is expected that the elimination of the axial Met donor interaction would preferentially stabilize the reduced Cu(I) state. A number of mutagenesis studies (13Karlsson B.G. Aasa R. Malmström B.G. Lundberg L.G. FEBS Lett. 1989; 253: 99-102Crossref Scopus (74) Google Scholar, 14Pascher T. Karlsson B.G. Nordling M. Malmström B.G. Vanngard T. Eur. J. Biochem. 1993; 212: 289-296Crossref PubMed Scopus (149) Google Scholar, 15Romero A. Hoitink C.W.G. Nar H. Huber R. Messerschmidt A. Canters G.W. J. Mol. Biol. 1993; 229: 1007-1021Crossref PubMed Scopus (165) Google Scholar) have been performed on the T1 copper site in azurin, and it was found that the nature of the axial ligand can influence E° to some extent. Mutation of Met-121 was found to tune the E° over a range of −0.105 V to 0.138 V with respect to the E° of the wild-type (wt) azurin at pH 7.0. The present study utilized site-directed mutagenesis to examine how the composition of the amino acid residues in the vicinity of the T1 copper affect the structure and E° of this copper in aTrametes villosa laccase (TvL) (16Yaver D.S. Xu F. Golightly E.J. Brown K.M. Brown S.H. Rey M.W. Schneider P. Halkier T. Mondorf K. Dalbøge H. Appl. Environ. Microbiol. 1996; 62: 834-841Crossref PubMed Google Scholar). We were also interested in determining how the mutations would impact the enzymatic properties,k cat, K m, and the pH dependence of enzymatic activity. TvL has a primary structure and redox/enzymatic properties very similar to the Trametes (Polyporus or Coriolus) versicolor laccase (PvL), an enzyme that has been extensively studied and is regarded as a representative high E° laccase (1Mayer A.M. Phytochemistry. 1987; 26: 11-20Crossref Scopus (703) Google Scholar, 2Messerschmidt A. Huber R. Eur. J. Biochem. 1990; 187: 341-352Crossref PubMed Scopus (386) Google Scholar, 3Solomon E.I. Machonkin T.E. Sundaram U.M. Messerschmidt A. Multi-Copper Oxidases. World Scientific, Singapore1997: 103-128Crossref Google Scholar, 4$$Google Scholar). We mutated Phe-463, which corresponds to the axial Met-517 in zAO, and two other residues (Glu-460 and Ala-461), corresponding to the His-514 and Met-515 in zAO (Table I). Our results showed that the F463M mutation led to significant changes in the T1 copper site, decreased the E°, and altered k catand K m. Underlined letters represent the mutated residues of this study. *, ligand to T3 copper; ‡, ligand to T1 copper. We thank Drs. Alan V. Klotz, Glenn E. Nedwin, Anders H. Pedersen, and Ejner B. Jensen of Novo Nordisk for critical reading and helpful suggestions, as well as Kimberly M. Brown, Michael W. Rey, Elizabeth J. Golightly, and Sheryl Bernauer of Novo Nordisk Biotech for carrying out protein/DNA sequencing." @default.
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• W1973074311 title "Targeted Mutations in a Trametes villosa Laccase" @default.
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