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Biomedical subjects

G Curzon

Publications and source records attributed to G Curzon.

At least 235 records · Page 13Linked to original sources
PubMed1969

Effects of immobilization on rat liver tryptophan pyrrolase and brain 5-hydroxytryptamine metabolism.

1. Rat liver tryptophan pyrrolase increased on immobilization. The concentration of 5-hydroxyindoleacetic acid in the brain also rose and that of 5-hydroxytryptamine fell.2. When adrenalectomized rats were immobilized pyrrolase activity did not rise and brain 5-hydroxytryptamine concentration fell to a lesser extent but the 5-hydroxyindoleacetic acid concentration rose as in intact animals.3. When intact rats were injected with the pyrrolase inhibitor Allopurinol both the increase of pyrrolase and the fall of 5-hydroxytryptamine on immobilization were less prominent but the concentration of 5-hydroxyindoleacetic acid rose as before. Allopurinol did not affect the changes in immobilized adrenalectomized rats.4. Immobilization thus appears to cause (a) decreased brain 5-hydroxytryptamine synthesis resulting from pyrrolase induction and (b) increased 5-hydroxytryptamine breakdown by a more direct effect on the brain. Results of experiments on rats injected with lysergic acid diethylamide, and with alpha-methyltryptophan or probenecid are consistent with the above interpretation.5. The 5-hydroxytryptamine and 5-hydroxyindoleacetic acid changes were maximal after 5-6 hours' immobilization and became less on more prolonged immobilization, which suggests regulatory changes.

Adrenalectomy↗
PubMed1968

The inhibition of caeruloplasmin by cyanide.

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.

Azides↗
PubMed1968

The effects of inhibitor mixtures and the specific effects of different anions on the oxidase activity of caeruloplasmin.

1. The interpretation of the effects of mixtures of inhibitors on enzymes is considered. 2. The effects of inhibitor mixtures on caeruloplasmin were determined. 3. Fluoride, chloride and cyanate inhibit at one type of site (alpha), whereas bromide and iodide inhibit at another type (beta) present in the same enzyme intermediate. 4. Effects of inhibitor mixtures containing azide or cyanide are consistent with previous indications (Speyer & Curzon, 1968) that these ligands form inhibited complexes with different enzyme intermediates. 5. Isobols of halides or of cyanate with azide indicate that azide inhibits caeruloplasmin by bridging two alpha sites, these being reduced copper atoms. 6. Iodide and cyanate give hyperbolic plots of 1/v against [I]. 7. It is suggested that in the cyanate-inhibited complex the inhibitor binds to a reduced copper atom (alpha site) but that binding of cyanate at another copper atom is sterically prevented. It is suggested that the less bulky alpha-site inhibitors, fluoride and chloride, cause complete inhibition by binding to both of these copper atoms, which can also be bridged by a single azide group. 8. Each halide shows a pattern of effects on caeruloplasmin that is qualitatively distinct from that of other halides.

Azides↗
PubMed1967

The oxidation of NN-dimethyl-p-phenylenediamine by oxidizing agents and by caeruloplasmin.

1. The oxidation of NN-dimethyl-p-phenylenediamine (DPD) by inorganic oxidants and by caeruloplasmin was studied. Some experiments were also made with NNN'N'-tetramethyl-p-phenylenediamine (TPD). 2. E(mM) (550) of the first free radical oxidation product of DPD (DPD(+)) was 9.8 and E(mM) (563) of the corresponding product of TPD (TPD(+)) was 12.5. 3. The non-enzymic decomposition of DPD(+) was studied with respect to temperature, pH, concentration and DPD/DPD(+) ratio, thus defining conditions for enzyme experiments under which DPD(+) extinction at 550mmu was proportional to enzyme activity. 4. Rates of oxidation of DPD to DPD(+) by caeruloplasmin were constant over a range of DPD concentrations. At low DPD concentrations a lag period occurred, which was eliminated by addition of DPD(+). 5. A lag period was not observed with TPD, but at low TPD concentrations the rate of TPD(+) formation was greater when TPD(+) was added. This suggests that TPD(+) may compete weakly as a substrate with TPD and may be oxidized further by the enzyme before a non-enzymic reaction with TPD to form more TPD(+). 6. With DPD sulphate or acetate or TPD sulphate as substrate, Lineweaver-Burk plots were curved. With DPD hydrochloride the chloride ion caused inhibition at higher concentrations, opposing the curvature. 7. Curved Lineweaver-Burk plots were interpreted in terms of two types of substrate binding site with different K(m) values but similar V(max.) values. 8. The apparent thermodynamic changes associated with enzyme-substrate-complex formation at the sites with higher K(m) suggest that considerable conformational change may occur on binding at these sites. 9. With substrate concentrations at which only the low-K(m) sites are involved 2mol. of DPD(+)/mol. of caeruloplasmin are formed before a steady state is established. At higher substrate concentrations up to 3.2mol. of DPD(+)/mol. of caeruloplasmin are formed at this initial stage. 10. Results are discussed in relation to caeruloplasmin structures in which (a) two valence-changing and two permanently cuprous copper atoms are more accessible than the remaining four copper atoms or (b) binding of substrate at one site hinders access of substrate to another site.

Aniline Compounds↗
PubMed1967

Inhibitors of caeruloplasmin.

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.

Azides↗
PubMed1966

The inhibition of caeruloplasmin by azide.

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.

Acetates↗
PubMed1965

An investigation of the decolorization of caeruloplasmin by acid.

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.

Journal Article↗
PubMed1965

Excretion of tryptophan metabolites in Friedreich's ataxia.

The overnight urinary excretions of the tryptophan metabolites 5-hydroxy indole acetic acid (5HIAA), indole acetic acid (IAA), indoxyl sulphate, and kynurenine were determined in 10 cases of Friedreich's ataxia and in 11 controls. Levels of 5HIAA and IAA were slightly lower and of indoxyl sulphate higher than in the controls but within normal limits; kynurenine was normal.A tryptophan load test subsequently given to four patients and three controls showed no significant abnormality in IAA, 5HIAA, indoxyl sulphate, and kynurenine.A specific abnormality in tryptophan metabolism in Friedreich's ataxia suggested by other workers was not observed.

Friedreich Ataxia↗