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Inhibitors of caeruloplasmin.

ABSTRACT: 1. A method is described by which substances inhibiting caeruloplasmin oxidase activity directly may be distinguished from those acting on stimulatory contaminant iron or on the product of enzyme action. 2. Many previously reported inhibitors, including saturated aliphatic carboxylates, hydrazines, 1,10-phenanthroline, borate and various psycho-active drugs, are found either not to act on the enzyme or to inhibit it only weakly. 3. A series of inorganic anions are compared as inhibitors. Anions such as azide and cyanide with strong copper-binding properties are the most effective inhibitors. There is a general inverse relationship between anion size and inhibitory power. Iodide is anomalous, the order of effectiveness of halides being F(-)>I(-)[unk]Cl(-)>Br(-). 4. Multidentate copperchelating ligands have little inhibitory effect. 5. A group of substances containing the structural unit [unk]C=[unk].CO(2)H, including fumarate and benzoate, cause inhibition. 6. Relative inhibitions by a series of mono-substituted benzoates are inversely related to molecular size. 7. Results are discussed in relation to earlier work on the disposition and function of the copper atoms of caeruloplasmin.

SUBMITTER: Curzon G

PROVIDER: S-EPMC1198295 | biostudies-other | 1967 Oct

REPOSITORIES: biostudies-other

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Copper:caeruloplasmin ratio.

Project description:Investigation of copper status can be a diagnostic challenge. The non-caeruloplasmin-bound copper (NCC) has deficiencies; accordingly, the copper:caeruloplasmin ratio has been suggested as an alternative index of copper status. A reference interval for this index was derived. In addition to making the interpretation of copper easier, the copper:caeruloplasmin ratio should also enable adjustment for relatively high caeruloplasmin concentrations without recourse to producing gender- and age-derived intervals. The copper:caeruloplasmin ratio has weaknesses similar to those identified for NCC in that immunological methods used for caeruloplasmin can cross react with apocaeruloplasmin and there is no standardised method for caeruloplasmin. Caeruloplasmin assays also have uncertainty from precision, bias and specificity and, accordingly, method-related differences may have a large effect on the copper:caeruloplasmin ratio in a manner similar to the NCC.

| S-EPMC2001115 | biostudies-other

Purification and properties of bovine caeruloplasmin.

Project description:A novel method is reported for isolation of bovine caeruloplasmin from plasma; it involves a rapid and mild procedure, namely two column chromatographies with stepwise elution and one (NH4)2SO4 precipitation, and results in a proteolytically undegraded homogeneous protein. The general structure of the protein, as evaluated by molecular-weight determination and amino acid composition, is very similar to that established for human and rat caeruloplasmin. Copper determination and e.p.r. spectral analysis on the native and NO-treated protein gave a metal-to-protein stoichiometry of six atoms of copper per molecule. Three copper atoms were detectable by e.p.r., with Type 2/Type 1 ratio = 1 : 3 in most samples. The protein is very sensitive to storage and/or handling. A component was isolated from aged samples, which was found to contain approximately four copper atoms per 125000 daltons, two of which were detectable by e.p.r. with the characters of Type 2 copper. However, the same component was found to be present, although to a lesser extent, in the fresh preparation and does not seem to be related to proteolytic degradation. This component has no oxidase activity. On the basis of these results it is suggested that caeruloplasmin molecules are intrinsically heterogeneous with respect to both copper content and copper type, and this can explain the intriguing stoichiometry regarding the different types of copper centres.

| S-EPMC1163423 | biostudies-other

The inhibition of caeruloplasmin by cyanide.

Project description:1. The reversible inhibition of the oxidase activity of caeruloplasmin by cyanide was investigated. 2. The kinetics are unusual, being competitive but with the inhibited complex formed only during cycling. 3. Inhibitory concentrations of cyanide are comparable with that of caeruloplasmin. 4. One azide group completely inhibits a caeruloplasmin molecule but two cyanide groups are required. 5. The results suggest that azide binds to a half-reduced or fully reduced conformational isomer of the enzyme whereas cyanide binds to completely reoxidized isomers, and that inhibited complexes contain ligand bridges between copper atoms.

| S-EPMC1198594 | biostudies-other

The inhibition of caeruloplasmin by azide.

Project description:1. The inhibition of the oxidase activity of caeruloplasmin by azide was investigated at 25 degrees and 7.5 degrees . 2. The inhibition is reversible on dilution or Sephadex treatment, indicating a caeruloplasmin-azide complex. 3. The enzyme is protected against azide inhibition by chloride, acetate or EDTA, the last-named acting not by chelation but by a non-specific effect similar to that of acetate. 4. Lineweaver-Burk plots with different concentrations of azide are parallel. This may occur either when the enzyme-substrate complex or when a subsequent intermediate structure of the enzyme forms the inhibited complex. 5. At 7.5 degrees inhibition may be shown not to occur until after the initial reaction of enzyme with substrate. 6. At 7.5 degrees , the inhibition is of the mutual-depletion type, inhibitory concentrations of azide being comparable with the concentration of caeruloplasmin. It is shown that the binding of a single azide group completely inhibits a caeruloplasmin molecule. 7. An arrangement of the four valence-changing copper atoms of caeruloplasmin is proposed in which they are so close together in the cuprous form that reoxidation may occur by the simultaneous transfer of four electrons from the copper atoms to a single oxygen molecule.

| S-EPMC1265135 | biostudies-other

Caeruloplasmin biosynthesis by the human uterus.

Project description:The blue copper protein caeruloplasmin is synthesized mainly by hepatocytes. An alternative transcript for caeruloplasmin produced in certain extrahepatic tissues, CP-1, contains an additional 12 nucleotides encoding 4 amino acids not present in the hepatic transcript, CP-2 [Yang, Friedrichs, Cupples, Bonifacio, S Sanford, Horton & Bowman (1990) J. Biol. Chem. 265, 10780-10785]. We have demonstrated transcription of caeruloplasmin mRNA by a well-differentiated human uterine epithelial adenocarcinoma cell line, Ishikawa, and by human uterine endometrium and purified endometrial glands. Identical CP-2 nucleotide sequences were obtained for partial caeruloplasmin transcripts from human liver and Ishikawa cells, indicating that CP-2 transcripts are produced by uterine epithelial lining cells. The synthesis of caeruloplasmin protein was demonstrated for Ishikawa cells and another uterine adenocarcinoma cell line, ECC1. Peptide-mapping analysis indicated that caeruloplasmin secreted by Ishikawa cells was structurally identical with the protein synthesized by the human hepatoblastoma cell line HepG2. The secretion of a 135,000-M(r) caeruloplasmin by Ishikawa and ECC1 cells, comparable with that of the human hepatoblastoma cell line, HepG2, indicated similar processing of uterine and hepatic caeruloplasmin. Incorporation of 67Cu into caeruloplasmin was demonstrated for Ishikawa and ECC1 cells, suggesting that the human uterus produces a bioactive form of caeruloplasmin and possesses the necessary metal transporters and intracellular machinery for copper incorporation into this protein.

| S-EPMC1132061 | biostudies-other

The inhibition of lipid autoxidation by human caeruloplasmin.

Project description:1. Purified caeruloplasmin was shown to inhibit lipid autoxidation induced by ascorbic acid or inorganic iron in the following systems: (a) an emulsion of linolenic acid in water; (b) an untreated ox brain homogenate in phosphate buffer; (c) a similar homogenate whose susceptibility to autoxidation had been abolished by dialysis or by heating and then restored by the above pro-oxidants. 2. The optimum conditions for this antioxidant activity were studied. 3. Caeruloplasmin did not inhibit autoxidation by u.v. irradiation in dialysed or preheated homogenates. 4. The apoprotein (without copper) had no antioxidant activity, whereas CuSO4 alone was much less effective as an antioxidant. 5. Iron-free transferrin also had some antioxidant activity.

| S-EPMC1183762 | biostudies-other

Ferritin does not accumulate iron oxidized by caeruloplasmin.

Project description:Ferritin is an iron-storage protein ubiquitous in mammals, plants and bacteria. It can be reconstituted, in vitro, from the apoprotein and Fe(II) salts in the presence of dissolved oxygen. Recently it has been reported that caeruloplasmin can facilitate apoferritin reconstitution and that iron oxidized by caeruloplasmin is sequestered within the ferritin shell. Here we show that the primary effect of adding caeruloplasmin to horse spleen ferritin during reconstitution is the competition between the two molecules for the iron. This competition results in overall increased rates of iron oxidation and a mixture of products, namely iron-containing ferritin and iron hydroxy polymers attached to caeruloplasmin. Iron oxidized by caeruloplasmin is not incorporated, to any significant extent, into horse spleen ferritin.

| S-EPMC1136423 | biostudies-other

A method for obtaining linear reciprocal plots with caeruloplasmin and its application in a study of the kinetic parameters of caeruloplasmin substrates.

Project description:1. The curved plots of 1/v against 1/[S] obtained when caeruloplasmin oxidizes NN-dimethyl-p-phenylenediamine were investigated. The first free-radical oxidation product of caeruloplasmin oxidation of NN-dimethyl-p-phenylenediamine is required for curvature, as straight-line plots were obtained when activities were measured either before appreciable free-radical product had appeared or in the presence of ascorbate, which reduced it back to NN-dimethyl-p-phenylenediamine. 2. In the presence of ascorbate linear reciprocal-plots were obtained with all of the 37 substrates tested. V(max.) values varied over only an eightfold range and those for the 20 p-amino compounds over only a twofold range. K(m) values, however, varied over a 10(4)-fold range. The small range of V(max.) values indicates that the rate-limiting step in caeruloplasmin action is relatively independent of the nature of the substrate. K(m) values suggest that substrates bind primarily by ring electrons, although certain side-chain groups increased the K(m) in a manner unrelated to likely changes of ring-electron densities. A mechanism involving repulsion between negative charges on the substrate and the enzyme was supported by the variation of the K(m) of 5-hydroxyindol-3-ylacetic acid with pH.

| S-EPMC1174077 | biostudies-other

An investigation of the decolorization of caeruloplasmin by acid.

Project description:1. The acid decolorization of caeruloplasmin was studied at various temperatures and pH values. 2. Two decolorization reactions may be distinguished: (i) an irreversible reaction with the thermodynamic characteristics of a protein denaturation; (ii) the attainment of an equilibrium between blue and colourless forms of caeruloplasmin with apparent pK 3.7 at 25 degrees . 3. The low temperature-dependence of the equilibrium suggests that it does not involve a gross denaturative change. 4. The reversible decolorization occurred both aerobically and anaerobically, indicating that the change does not involve dissociation of a copper-oxygen complex. 5. Spectral changes during the decolorization are described. 6. The changes occurring during acid decolorization are discussed in relation to a formal model of the gross structure of caeruloplasmin.

| S-EPMC1264555 | biostudies-other

Adjusting copper concentrations for caeruloplasmin levels in routine clinical practice.

Project description:BACKGROUND: An investigation on copper metabolism usually includes the measurement of serum levels of copper and caeruloplasmin. Using these levels, some laboratories derive levels of non-caeruloplasmin-bound copper (NCC); however, a considerable number of patients may show negative values, which is not physiologically possible. AIM: To derive an equation for adjusted copper in a manner similar to that widely accepted for adjusted calcium. METHODS: A linear regression equation for the relationship between caeruloplasmin and copper was used: [copper] (micromol/l) = 0.052x[caeruloplasmin] (mg/l). An equation for copper adjusted for caeruloplasmin was derived using this equation and the reference interval of 10-25 micromol/l for copper. RESULTS: The derived equation was [adjusted copper] (micromol/l) = [total copper] (micromol/l)+0.052x[caeruloplasmin] (mg/l)+17.5 (micromol/l). The adjusted copper concentrations on the 2.5th and 97.5th centiles were 12.7 and 21.5 micromol/l, respectively, with the population having a gaussian distribution. The relationship between NCC and the adjusted copper concentrations is linear and independent of caeruloplasmin concentration. CONCLUSION: Calculation of copper adjusted for caeruloplasmin uses the same variables as those for NCC. Accordingly, the problems that are caused by the lack of specificity of caeruloplasmin immunoassays are the same as those identified for NCC. This calculation, however, overcomes the negative values that are found in a considerable minority of patients with NCC, as well as age and sex differences in the caeruloplasmin reference interval. As the concept is already familiar to non-laboratory healthcare professionals in the form of calcium adjusted for albumin, this method is potentially less confusing than that for NCC.

| S-EPMC1860450 | biostudies-other

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