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  • 1
    Online Resource
    Online Resource
    Phenolic substrates and suicide inactivation of tyrosinase: kinetics and mechanism
    Portland Press Ltd. ; 2008
    In:  Biochemical Journal Vol. 416, No. 3 ( 2008-12-15), p. 431-440
    Details
    In: Biochemical Journal, Portland Press Ltd., Vol. 416, No. 3 ( 2008-12-15), p. 431-440
    Abstract: The suicide inactivation mechanism of tyrosinase acting on its substrates has been studied. The kinetic analysis of the proposed mechanism during the transition phase provides explicit analytical expressions for the concentrations of o-quinone against time. The electronic, steric and hydrophobic effects of the substrates influence the enzymatic reaction, increasing the catalytic speed by three orders of magnitude and the inactivation by one order of magnitude. To explain the suicide inactivation, we propose a mechanism in which the enzymatic form Eox (oxy-tyrosinase) is responsible for such inactivation. A key step might be the transfer of the C-1 hydroxyl group proton to the peroxide, which would act as a general base. Another essential step might be the axial attack of the o-diphenol on the copper atom. The rate constant of this reaction would be directly related to the strength of the nucleophilic attack of the C-1 hydroxyl group, which depends on the chemical shift of the carbon C-1 (δ1) obtained by 13C-NMR. Protonation of the peroxide would bring the copper atoms together and encourage the diaxial nucleophilic attack of the C-2 hydroxyl group, facilitating the co-planarity with the ring of the copper atoms and the concerted oxidation/reduction reaction, and giving rise to an o-quinone. The suicide inactivation would occur if the C-2 hydroxyl group transferred the proton to the protonated peroxide, which would again act as a general base. In this case, the co-planarity between the copper atom, the oxygen of the C-1 and the ring would only permit the oxidation/reduction reaction on one copper atom, giving rise to copper(0), hydrogen peroxide and an o-quinone, which would be released, thus inactivating the enzyme.
    Type of Medium: Online Resource
    ISSN: 0264-6021 , 1470-8728
    URL: Article
    DOI: 10.1042/BJ20080892
    RVK:
    WA 15000
    Language: English
    Publisher: Portland Press Ltd.
    Publication Date: 2008
    detail.hit.zdb_id: 1473095-9
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  • 2
    Online Resource
    Online Resource
    Deuterium isotope effect on the oxidation of monophenols and o-diphenols by tyrosinase
    Portland Press Ltd. ; 2004
    In:  Biochemical Journal Vol. 380, No. 3 ( 2004-06-15), p. 643-650
    Details
    In: Biochemical Journal, Portland Press Ltd., Vol. 380, No. 3 ( 2004-06-15), p. 643-650
    Abstract: A solvent deuterium isotope effect on the catalytic affinity (km) and catalytic constant (kcat) of tyrosinase in its action on different monophenols and o-diphenols was observed. The catalytic constant decreased in all substrates as the molar fraction of deuterated water in the medium increased, while the catalytic affinity only decreased for the o-diphenols with an R group in C-1 [-H, -CH3 and -CH(CH3)2]. In a proton inventory study of the oxidation of o-diphenols, the representation of kcatfn/kcatf0 against n (atom fractions of deuterium), where kcatfn is the catalytic constant for a molar fraction of deuterium (n) and kcatf0 is the corresponding kinetic parameter in a water solution, was linear for all substrates, indicating that only one of the four protons transferred from the hydroxy groups of the two molecules of substrate, which are oxidized in one turnover, is responsible for the isotope effects, the proton transferred from the hydroxy group of C-4 to the peroxide of the oxytyrosinase form (Eox). However, in the representation of Kmfn/Kmf0 against n, where Kmfn represents the catalytic affinity for a molar fraction of deuterium (n) and Kmf0 is the corresponding kinetic parameter in a water solution, a linear decrease was observed as n increased in the case of o-diphenols with the R group [-H, -CH3 and -CH(CH3)2] , and a parabolic increase with other R groups, indicating that more than one proton is responsible for the isotope effects on substrate binding. In the case of monophenols with six protons transferred in the catalytic cycle, the isotope effect occurs in the same way as for o-diphenols. In the present paper, the fractionation factors of different monophenols and o-diphenols are described and possible mechanistic implications are discussed.
    Type of Medium: Online Resource
    ISSN: 0264-6021 , 1470-8728
    URL: Article
    DOI: 10.1042/bj20040136
    RVK:
    WA 15000
    Language: English
    Publisher: Portland Press Ltd.
    Publication Date: 2004
    detail.hit.zdb_id: 1473095-9
    SSG: 12
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  • 3
    Online Resource
    Online Resource
    Study of stereospecificity in mushroom tyrosinase
    Portland Press Ltd. ; 1998
    In:  Biochemical Journal Vol. 331, No. 2 ( 1998-04-15), p. 547-551
    Details
    In: Biochemical Journal, Portland Press Ltd., Vol. 331, No. 2 ( 1998-04-15), p. 547-551
    Abstract: This paper reports experiments on the stereospecificity observed in the monophenolase and diphenolase activities of mushroom tyrosinase. Several enantiomorphs of monophenols and o-diphenols were assayed: l-tyrosine, d,l-tyrosine, d-tyrosine; l-α-methyltyrosine, d,l-α-methyltyrosine; l-dopa, d,l-dopa, d-dopa; l-α-methyldopa, d,l-α-methyldopa; l-isoprenaline, d,l-isoprenaline and d-isoprenaline. The Vmax values obtained for each series were the same. The electronic densities on the carbon atoms in the meta(C-3) and the para(C-4) positions of the benzene ring were determined by NMR assays. This value is related to the nucleophilic power of the oxygen atom belonging to the hydroxy group, which could explain the Vmax values experimentally obtained for the monophenolase and diphenolase activities of mushroom tyrosinase. The spatial orientation of the ring substituents led to lower Km values for l-isomers than for d-isomers. However, the Vmax values were the same for each series of isomers because spatial orientation did not affect the NMR value of C-4. Therefore mushroom tyrosinase showed stereospecificity in its affinity towards its substrates (Km) but not in the transformation reaction rate (Vmax) of these substrates.
    Type of Medium: Online Resource
    ISSN: 0264-6021 , 1470-8728
    URL: Article
    DOI: 10.1042/bj3310547
    RVK:
    WA 15000
    Language: English
    Publisher: Portland Press Ltd.
    Publication Date: 1998
    detail.hit.zdb_id: 1473095-9
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  • 4
    Online Resource
    Online Resource
    Differential expression of circulating miRNAs as a novel tool to assess BAG3-associated familial dilated cardiomyopathy
    Portland Press Ltd. ; 2019
    In:  Bioscience Reports Vol. 39, No. 3 ( 2019-03-29)
    Details
    In: Bioscience Reports, Portland Press Ltd., Vol. 39, No. 3 ( 2019-03-29)
    Abstract: A new familial dilated cardiomyopathy (FDCM) was found related to mutations in BAG3 gene. MicroRNAs (miRNAs) represent new targets of FDCM, although no studies have assessed clinical association between Bcl2-associated athanogene 3 (BAG3)-related DCM and miRNAs. Here, we studied whether a clinical association between BAG3-related FDCM and circulating miRNAs may have diagnostic and prognostic value in a small cohort of familial related individuals carrying a BAG3 mutation (BAG3+) and/or diagnosed of dilated cardiomyopathy (DCM) (DCM+). The analysis of 1759 circulating miRNAs showed significant differences between BAG3+ and BAG3- individuals for miRNAs mir-3191-3p, 6769b-3p, 1249-ep, 154-5p, 6855-5p, and 182-5p, while comparisons between BAG3+/DCM+ versus BAG3+/DCM- were restricted to miRNAs mir-154-5p, 6885-5p, and 182-5p, showing significant correlation with systolic and diastolic blood pressure, A wave, left atrium length, and left atrium area. Additionally, when stratified by gender and age, miRNAs were statistically correlated with critical parameters, including left ventricle ejection fraction (LVEF) and ventricular diameter, in women and young men. Likewise, 56% of BAG3+/DCM+, significantly co-expressed mir-154-5p and mir-182-5p, and a slight 4% did not express such combination, suggesting that co-expression of mir-154-5p and mir-182-5p may potentially show diagnostic value. Further studies will require long-term follow-up, and validation in larger populations.
    Type of Medium: Online Resource
    ISSN: 0144-8463 , 1573-4935
    URL: Article
    DOI: 10.1042/BSR20180934
    Language: English
    Publisher: Portland Press Ltd.
    Publication Date: 2019
    detail.hit.zdb_id: 2014993-1
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  • 5
    Online Resource
    Online Resource
    Molecular mechanism for catalysis by a new zinc-enzyme, dopachrome tautomerase
    Portland Press Ltd. ; 1996
    In:  Biochemical Journal Vol. 313, No. 2 ( 1996-01-15), p. 447-453
    Details
    In: Biochemical Journal, Portland Press Ltd., Vol. 313, No. 2 ( 1996-01-15), p. 447-453
    Abstract: Dopachrome tautomerase (DCT; EC 5.3.3.12) catalyses the conversion of L-dopachrome into 5,6-dihydroxyindole-2-carboxylic acid in the mammalian eumelanogenic biosynthetic pathway. This enzyme, also named TRP2, belongs to a family of three metalloenzymes termed the tyrosinase-related proteins (TRPs). It is well known that tyrosinase has copper in its active site. However, the nature of the metal ion in the active site of DCT is under discussion. Whereas theoretical predictions based on similarity between the protein sequences of the TRPs suggest the presence of copper, the different inhibition pattern of DCT with some metal chelators compared with that of tyrosinase suggests that the nature of the metal ion could differ. Direct estimations of the metal content in purified DCT preparations show the presence of around 1.5 Zn atoms/molecule and the absence of copper. Apoenzyme preparation by treatment of DCT with cyanide or o-phenanthroline followed by reconstitution experiments of tautomerase activity in the presence of different ions confirmed that the metal cofactor for the DCT active site is zinc. Our results are consistent with Zn2+ chelation by the highly conserved histidine residues homologous to the histidines at the classical copper-binding sites in tyrosinase. This finding accounts for the reaction catalysed by DCT, i.e. a tautomerization, versus the copper-mediated oxidations catalysed by tyrosinase. Based on the predicted tetrahedrical co-ordination of the zinc ions in the enzyme active site, a molecular mechanism for the catalysis of L-dopachrome tautomerization is proposed. From the present data, the existence of additional ligands for metal ions other than zinc in the DCT molecule, such as the proposed cysteine iron-binding sites, cannot be completely ruled out. However, if such sites exist, they could be subsidiary binding sites, whose function would be likely to stabilize the protein.
    Type of Medium: Online Resource
    ISSN: 0264-6021 , 1470-8728
    URL: Article
    DOI: 10.1042/bj3130447
    RVK:
    WA 15000
    Language: English
    Publisher: Portland Press Ltd.
    Publication Date: 1996
    detail.hit.zdb_id: 1473095-9
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  • 6
    Online Resource
    Online Resource
    The 5,6-dihydroxyindole-2-carboxylic acid (DHICA) oxidase activity of human tyrosinase
    Portland Press Ltd. ; 2001
    In:  Biochemical Journal Vol. 354, No. 1 ( 2001-02-15), p. 131-139
    Details
    In: Biochemical Journal, Portland Press Ltd., Vol. 354, No. 1 ( 2001-02-15), p. 131-139
    Abstract: Melanin synthesis in mammals is catalysed by at least three enzymic proteins, tyrosinase (monophenol dihydroxyphenylalanine:oxygen oxidoreductase, EC 1.14.18.1) and tyrosinase-related proteins (tyrps) 1 and 2, whose genes map to the albino, brown and slaty loci in mice, respectively. Tyrosinase catalyses the rate-limiting generation of l-dopaquinone from l-tyrosine and is also able to oxidize l-dopa to l-dopaquinone. Conversely, mouse tyrp1, but not tyrosinase, catalyses the oxidation of the indolic intermediate 5,6-dihydroxyindole-2-carboxylic acid (DHICA) into the corresponding 5,6-indolequinone-2-carboxylic acid, thus promoting the incorporation of DHICA units into eumelanin. The catalytic activities of the human melanogenic enzymes are still debated. TYRP1has been reported to lack DHICA oxidase activity, whereas tyrosinase appears to accelerate DHICA consumption, thus raising the question of DHICA metabolism in human melanocytes. Here we have used two different approaches, comparison of the catalytic activities of human melanocytic cell lines expressing the full set of melanogenic enzymes or deficient in TYRP1, and transient expression of TYR and tyr genes in COS7 cells, to demonstrate that human tyrosinase actually functions as a DHICA oxidase, as opposed to the mouse enzyme. Therefore, human tyrosinase displays a broader substrate specificity than its mouse counterpart, and might be at least partially responsible for the incorporation of DHICA units into human eumelanins.
    Type of Medium: Online Resource
    ISSN: 0264-6021 , 1470-8728
    URL: Article
    DOI: 10.1042/bj3540131
    RVK:
    WA 15000
    Language: English
    Publisher: Portland Press Ltd.
    Publication Date: 2001
    detail.hit.zdb_id: 1473095-9
    SSG: 12
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  • 7
    Online Resource
    Online Resource
    The 5,6-dihydroxyindole-2-carboxylic acid (DHICA) oxidase activity of human tyrosinase
    Portland Press Ltd. ; 2001
    In:  Biochemical Journal Vol. 354, No. 1 ( 2001-2-15), p. 131-
    Details
    In: Biochemical Journal, Portland Press Ltd., Vol. 354, No. 1 ( 2001-2-15), p. 131-
    Type of Medium: Online Resource
    ISSN: 0264-6021
    URL: Article
    DOI: 10.1042/0264-6021:3540131
    RVK:
    WA 15000
    Language: Unknown
    Publisher: Portland Press Ltd.
    Publication Date: 2001
    detail.hit.zdb_id: 1473095-9
    SSG: 12
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  • 8
    Online Resource
    Online Resource
    Kinetic study of the inactivation of ascorbate peroxidase by hydrogen peroxide
    Portland Press Ltd. ; 2000
    In:  Biochemical Journal Vol. 348, No. 2 ( 2000-6-1), p. 321-
    Details
    In: Biochemical Journal, Portland Press Ltd., Vol. 348, No. 2 ( 2000-6-1), p. 321-
    Type of Medium: Online Resource
    ISSN: 0264-6021
    URL: Article
    DOI: 10.1042/0264-6021:3480321
    RVK:
    WA 15000
    Language: Unknown
    Publisher: Portland Press Ltd.
    Publication Date: 2000
    detail.hit.zdb_id: 1473095-9
    SSG: 12
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  • 9
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    Online Resource
    Kinetic study of the inactivation of ascorbate peroxidase by hydrogen peroxide
    Portland Press Ltd. ; 2000
    In:  Biochemical Journal Vol. 348, No. 2 ( 2000-06-01), p. 321-328
    Details
    In: Biochemical Journal, Portland Press Ltd., Vol. 348, No. 2 ( 2000-06-01), p. 321-328
    Abstract: The activity of ascorbate peroxidase (APX) has been studied with H2O2 and various reducing substrates. The activity decreased in the order pyrogallol & gt; ascorbate & gt; guaiacol & gt; 2,2ʹ-azino-bis-(3-ethylbenzthiazoline-6-sulphonic acid) (ABTS). The inactivation of APX with H2O2 as the sole substrate was studied. The number of H2O2 molecules required for maximal inactivation of the enzyme was determined as approx. 2.5. Enzymic activity of approx. 20% of the original remained at the end of the inactivation process (i.e. approx. 20% resistance) when ascorbate or ABTS was used as the substrate in activity assays. With pyrogallol or guaiacol no resistance was seen. Inactivation by H2O2 followed over time with ascorbate or pyrogallol assays exhibited single-exponential decreases in enzymic activity. Hyperbolic saturation kinetics were observed in both assay systems; a similar dissociation constant (0.8 μM) for H2O2 was obtained in each case. However, the maximum rate constant (λmax) obtained from the plots differed depending on the assay substrate. The presence of reducing substrate in addition to H2O2 partly or completely protected the enzyme from inactivation, depending on how many molar equivalents of reducing substrate were added. An oxygen electrode system has been used to confirm that APX does not exhibit a catalase-like oxygen-releasing reaction. A kinetic model was developed to interpret the experimental results; both the results and the model are compared and contrasted with previously obtained results for horseradish peroxidase C. The kinetic model has led us to the conclusion that the inactivation of APX by H2O2 represents an unusual situation in which no enzyme turnover occurs but there is a partition of the enzyme between two forms, one inactive and the other with activity towards reducing substrates such as ascorbate and ABTS only. The partition ratio is less than 1.
    Type of Medium: Online Resource
    ISSN: 0264-6021 , 1470-8728
    URL: Article
    DOI: 10.1042/bj3480321
    RVK:
    WA 15000
    Language: English
    Publisher: Portland Press Ltd.
    Publication Date: 2000
    detail.hit.zdb_id: 1473095-9
    SSG: 12
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