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11 recordsLinked to original sources
PubMed1994

Ascorbate based novel high affinity alternate reductants and competitive inhibitors of dopamine beta-monooxygenase.

A series of ascorbate derivatives has been used to examine the specificity and the chemistry of the reduction site of dopamine beta-monooxygenase (D beta M). Replacement of the 6-OH group of ascorbic acid with either bromine or hydrogen does not alter the enzyme reduction efficiency significantly. Unexpectedly, the 6-OH modified ascorbate derivatives, 6-S-phenyl-6-thio-L-ascorbic acid and 6-O-phenyl-L-ascorbic acid were found to have much higher affinity for the enzyme than the most effective known electron donor, ascorbic acid (AscH-). The affinity of 2-amino-6-S-phenyl-L-ascorbic acid was found to be similar to that of 2-amino-L-ascorbic acid. 6-Amino-6-deoxy-L-ascorbic acid is neither a substrate nor an inhibitor for the enzyme. Although glucoascorbic acid is an excellent substrate for the enzyme, imino glucoascorbic acid was found to be an extremely potent competitive inhibitor for the enzyme. The stereoelectronic properties and alternate binding modes of these molecules have been considered in explaining the observations.

Adrenal Medulla↗
PubMed1994

Substrate specificity of ascorbate oxidase: unexpected similarity to the reduction site of dopamine beta-monooxygenase.

A series of ascorbate derivatives has been used to examine the specificity of the reduction site of ascorbate oxidase. Replacement of the 6-OH group of ascorbic acid with either hydrogen or bromine does not alter the substrate activity significantly. 6-Amino-6-deoxy-L-ascorbic acid is a weak substrate for the enzyme, suggesting that positively charged groups at the 6-position are not well tolerated by the enzyme. The modification of the 5-OH reduces the effective interaction with the enzyme and the replacement of 6-OH with 6-S-phenyl- or 6-O-phenyl groups significantly increases the affinity for the enzyme. Both 2-Amino-6-S-phenyl-L-ascorbic acid and imino-D-glucoascorbic acid are not substrates for the enzyme. The stereoelectronic properties and alternate binding modes of these molecules are being considered to explain these observations. The substrate specificity of the enzyme is compared to the specificity of the reduction site of dopamine beta-monooxygenase.

Ascorbate Oxidase↗
PubMed1975

The effects of ascorbic acid deficiency on calcium and collagen metabolism in cultured fetal rat bones.

The effects of ascorbic acid deficiency on growth and calcification of bone were studied in whole 18-day fetal rat radii and ulnae cultured in a chemically defined medium. Ascorbic acid deficiency decreased the formation of labeled hydroxyporline from labeled proline in both bone shafts and cartilage ends while incorporation of tryptophan was maintained. Dry weights and collagen content of bone and cartilage were decreased, but calcification was not affected. The optimun initial concentration of ascorbic acid for collagen synthesis was 200 mug/ml. The effect of ascorbic acid was not antagonized by glucoascorbic acid or replaced by dithiothreitol. Decreased collagen synthesis in ascorbic acid deficiency could not be ascribed to loss of available peptidyl proline hydorxylase. Formation of underhydroxylated collagen and its release into the medium accounted for much of the decrease in hydroxylated collagen in ascorbic acid deficient bones. Nevertheless, the total newly synthesized collagen, as measured by collagenase digestion, was still decreased. Similar effects were exerted by alpha, alpha'-dipyridyl which also inhibited general protein synthesis. Ascorbic acid did not stimulate proline incorporation into collagen in the presence of alpha, alpha'-dipyridyl.

Animals↗
PubMed1995

The reduction of membrane-bound dopamine beta-monooxygenase in resealed chromaffin granule ghosts. Is intragranular ascorbic acid a mediator for extragranular reducing equivalents?

The role of internal and external reductants in the dopamine beta-monooxygenase (D beta M)-catalyzed conversion of dopamine to norepinephrine has been investigated in resealed chromaffin granule ghosts. The rate of norepinephrine production was not affected by the exclusion of internal ascorbate. The omission of ascorbate from the external medium drastically reduced the norepinephrine production without affecting the net rate of dopamine uptake. In the presence of the external reductant, the internal ascorbate levels were constant throughout the incubation period. The rate of norepinephrine production was not affected when ghosts were resealed to contain the D beta M reduction site inhibitor, imino-D-glucoascorbate. Ghosts incubated with external imino-D-glucoascorbate reduced the norepinephrine production. The weak D beta M reductant, 6-amino-L-ascorbic acid, was found to be a good external reductant for granule ghosts. The outcome of the above experiments was not altered when dopamine was replaced with the reductively inactive D beta M substrate, tyramine. These results and the known topology of membrane-bound D beta M disfavor the direct reduction of the enzyme by the external reductant. Our observations are consistent with the hypothesis that external ascorbate is the sole source of reducing equivalents for D beta M monooxygenation and that internal soluble ascorbate (or dopamine) may not directly reduce or mediate the reduction of membrane-bound D beta M in resealed granule ghosts.

Adenosine Triphosphate↗
PubMed1992

Stereospecific effects of ascorbic acid and analogues on D1 and D2 agonist binding.

Ascorbic acid inhibited the specific binding of both the D1 agonist, [3H] SKF 38393, and the D2 agonist, [3H] N-0437 at physiologically relevant concentrations. This inhibition was both stereospecific and receptor selective. Using ligand concentrations approximating their KD's, the IC50's for ascorbate and two structural analogues, isoascorbate and D-glucoascorbate, were determined. The rank order of IC50's at both D1 and D2 were D-glucoascorbate greater than isoascorbate greater than ascorbate. However, the IC50 for each compound was greater at D1 than D2. Evaluation of the relationship between the IC50 for ascorbate and the ligand concentration using both the D1 and the D2 ligand yielded data inconsistent with competitive inhibition models. Preliminary experiments were conducted to evaluate the site and type of inhibition with results consistent with an allostearic effect at the level of the receptor.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1986

Role of ascorbic acid in dopamine beta-hydroxylation. The endogenous enzyme cofactor and putative electron donor for cofactor regeneration.

The role(s) of ascorbic acid in dopamine beta-hydroxylation was studied in primary cultures of bovine adrenomedullary chromaffin cells and in isolated bovine adrenomedullary chromaffin vesicles. Dopamine beta-hydroxylase activity was assessed by measuring the rate of conversion of tyramine to octopamine. The ascorbic acid content of chromaffin cells declined with time in culture and the dopamine beta-hydroxylase activity of ascorbate-depleted cells was low. Ascorbate additions to ascorbate-depleted cells increased both the intracellular ascorbate concentrations and the rates of dopamine beta-hydroxylation. Ascorbate uptake into the cells was rapid; however, the onset of enhanced octopamine synthesis by added ascorbate was delayed by several hours and closely followed the time course for accumulation of the newly taken up ascorbate into the chromaffin vesicle. The amount of octopamine synthesized by the chromaffin cells exceeded the intracellular ascorbate content and ascorbate levels were maintained during dopamine beta-hydroxylation in the absence of external ascorbate. This suggests an efficient recycling of ascorbate. In contrast to intact cells, ascorbic acid was depleted during octopamine synthesis in isolated chromaffin vesicles. The molar ratio of octopamine formed to ascorbate depleted was close to unity. Thus, the recycling of intravesicular ascorbate depends on an extravesicular factor(s). The depletion of intravesicular ascorbate during dopamine beta-hydroxylation was prevented by the addition of nonpermeant extravesicular electron donors such as ascorbate or glucoascorbate. This suggests that intravesicular ascorbate is maintained in the reduced state by electron transport across the vesicle membrane. These results are compatible with the hypothesis that both intra- and extravesicular ascorbate participate in the regulation of dopamine beta-hydroxylase. Intravesicular ascorbate is the cofactor for the enzyme. Cytosolic ascorbate is most likely the electron donor for the vesicle-membrane electron transport system which maintains the intravesicular cofactor concentration.

Adrenal Medulla↗