Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: DrugBank:EXPT00568 (ascorbate)
 23,072 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Metabolism of 14C-labeled tryptophan and 3-hydroxyanthranilic acid were administered to early hepatoma patients to evaluate the conversion of these precursors to niacin metabolites and to assess the effect of dietary supplementation with vitamin B-6, riboflavin, thiamin and vitamin C on the extent of conversion. Expired labeled carbon dioxide and urinary excretion of picolinic acid (PA), quinolinic acid (QA), nicotinic acid (NA), N1-methylnicotinamide (N1MeNAm) and N1-methyl-2-pyridone-5-carboxamide (MPCA) were measured by carrier isolations. There were no consistent statistical differences in these conversions before and after vitamin supplementation, suggesting that the patients' nutrition was adequate and that none of the vitamins were rate-limiting under these conditions.
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PMID:Vitamin effects on tryptophan-niacin metabolism in primary hepatoma patients. 1072 Oct 67

Despite considerable worldwide efforts, no single etiology has been identified to explain the development of chronic fatigue syndrome (CFS). It is likely that multiple factors promote its development, sometimes with the same factors both causing and being caused by the syndrome. A detailed review of the literature suggests a number of marginal nutritional deficiencies may have etiologic relevance. These include deficiencies of various B vitamins, vitamin C, magnesium, sodium, zinc, L-tryptophan, L-carnitine, coenzyme Q10, and essential fatty acids. Any of these nutrients could be marginally deficient in CFS patients, a finding that appears to be primarily due to the illness process rather than to inadequate diets. It is likely that marginal deficiencies not only contribute to the clinical manifestations of the syndrome, but also are detrimental to the healing processes. Therefore, when feasible, objective testing should identify them and their resolution should be assured by repeat testing following initiation of treatment. Moreover, because of the rarity of serious adverse reactions, the difficulty in ruling out marginal deficiencies, and because some of the therapeutic benefits of nutritional supplements appear to be due to pharmacologic effects, it seems rational to consider supplementing CFS patients with the nutrients discussed above, along with a general high-potency vitamin/mineral supplement, at least for a trial period.
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PMID:Nutritional strategies for treating chronic fatigue syndrome. 1120 53

Glycolate oxidase that was partially purified from pea leaves was inactivated in vitro by blue light in the presence of FMN. Inactivation was greatly retarded in the absence of O2. Under aerobic conditions H2O2 was formed. The presence of catalase, GSH or dithiothreitol protected glycolate oxidase against photoinactivation. Less efficient protection was provided by ascorbate, histidine, tryptophan or EDTA. The presence of superoxide dismutase or of hydroxyl radical scavengers had no, or only minor, effects. Glutathione suppressed H2O2 accumulation and was oxidized in the presence of glycolate oxidase in blue light. Glycolate oxidase was also inactivated in the presence of a superoxide-generating system or by H2O2 in darkness. In intact leaves photoinactivation of glycolate oxidase was not observed. However, when catalase was inactivated by the application of 3-amino-1,2,4-triazole or depleted by prolonged exposure to cycloheximide a strong photoinactivation of glycolate oxidase was also seen in leaves. In vivo blue and red light were similarly effective. Furthermore, glycolate oxidase was photoinactivated in leaves when the endogenous GSH was depleted by the application of buthionine sulfoximine. Both catalase and antioxidants, in particular GSH, appear to be essential for the protection of glycolate oxidase in the peroxisomes in vivo.
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PMID:Photoinactivation and protection of glycolate oxidase in vitro and in leaves. 1092 47

Our recent in vitro results [4] indicate that cigarette smoke induces oxidation of human plasma proteins and extensive oxidative degradation of the guinea pig lung, heart, and liver microsomal proteins, which is almost completely prevented by ascorbic acid. In this paper, we substantiate the in vitro results with in vivo observations. We demonstrate that exposure of subclinical or marginal vitamin C-deficient guinea pigs to cigarette smoke causes oxidation of plasma proteins as well as extensive oxidative degradation of the lung microsomal proteins. Cigarette smoke exposure also results in some discernible damage of the heart microsomal proteins. The oxidative damage has been manifested by SDS-PAGE, accumulation of carbonyl and bityrosine, as well as loss of tryptophan and protein thiols. Cigarette smoke exposure also induces peroxidation of microsomal lipids as evidenced by the formation of conjugated dienes, malondialdehyde, and fluorescent pigment. Cigarette smoke-induced oxidative damage of proteins and peroxidation of lipids are accompanied by marked drop in the tissue ascorbate levels. Protein damage and lipid peroxidation are also observed in cigarette smoke-exposed pair-fed guinea pigs receiving 5 mg vitamin C/animal/day. However, complete protection against protein damage and lipid peroxidation occurs when the guinea pigs are fed 15 mg vitamin C/animal/day. Also, the cigarette smoke-induced oxidative damage of proteins and lipid is reversed after discontinuation of cigarette smoke exposure accompanied by ascorbate therapy. The results, if extrapolated to humans, indicate that comparatively large doses of vitamin C may protect the smokers from cigarette smoke-induced oxidative damage and associated degenerative diseases.
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PMID:Vitamin C prevents cigarette smoke-induced oxidative damage in vivo. 1098 Apr

The kinetics of O2*- reaction with semi-oxidized tryptophan radicals in lysozyme, Trp*(Lyz) have been investigated at various pHs and conformational states by pulse radiolysis. The Trp*(Lyz) radicals were formed by Br2*- oxidation of the 3-4 exposed Trp residues in the protein. At pH lower than 6.2, the apparent bimolecular rate is about 2 x 10(8) M(-1) s(-1); but drops to 8 x 10(7) M(-1) s(-1) or less above pH 6.3 and in CTAC micelles. Similarly, the apparent bimolecular rate constant for the intermolecular Trp*(Lyz) + Trp*(Lyz) recombination reaction is about (4-7 x 10(6) M(-1) s(-1)) at/or below pH 6.2 then drops to 1.3-1.6 x 10(6) M(-1) s(-1) at higher pH or in micelles. This behavior suggests important conformational and/or microenvironmental rearrangement with pH, leading to less accessible semi-oxidized Trp* residues upon Br2*- reaction. The kinetics of Trp*(Lyz) with ascorbate, a reducing species rather larger than O2*- have been measured for comparison. The well-established long range intramolecular electron transfer from Tyr residues to Trp radicals--leading to the repair of the semi-oxidized Trp*(Lyz) and formation of the tyrosyl phenoxyl radical is inhibited by the Trp*(Lyz) + O2*- reaction, as is most of the Trp*(Lyz) + Trp*(Lyz) reaction. However, the kinetic behavior of Trp*(Lyz) suggests that not all oxidized Trp residues are involved in the intermolecular recombination or reaction with O2*-. As the kinetics are found to be quite pH sensitive, this study demonstrates the effect of the protein conformation on O2*- reactivity. To our knowledge, this is the first report on the kinetics of a protein-O2*- reaction not involving the detection of change in the redox state of a prosthetic group to probe the reactivity of the superoxide anion.
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PMID:Interactions of superoxide anion with enzyme radicals: kinetics of reaction with lysozyme tryptophan radicals and corresponding effects on tyrosine electron transfer. 1102 47

The 2,2'-azobis(2-amidinopropane) (AAPH)-induced inactivation and oxidative modification of lysozyme, as determined by the loss of tryptophan-associated fluorescence (TAF) and the increase in dinitrophenylhydrazine-reactive carbonyl groups (CO), were studied in the absence and in the presence of antioxidants. AAPH induced a progressive inactivation of the enzyme and a parallel decrease of its TAF. Both changes were closely correlated (R2 = 0.97); however, the inactivation was only partially associated with an increase in CO. The latter reached maximal values at times half those needed to attain maximal losses in both lysozyme activity and TAF. A stoichiometric comparison reveals that whereas over 74% of the enzyme molecules had lost their activity, only 5% exhibited an increment in CO. CO formation was affected differentially by boldine and trolox. Both antioxidants fully protected against the early inactivation and loss of TAF; however, the increase in CO was completely unaffected by trolox. Exposure of lysozyme to Fe3+/ascorbate induced no loss of activity or TAF, but it led to an accumulation of CO similar to that induced by AAPH. Results indicate that CO formation and lysozyme inactivation are two mechanistically dissociable events and that changes in the former parameter can perfectly occur in the absence of changes in the latter.
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PMID:Free-radical-induced inactivation of lysozyme and carbonyl residue generation in protein are not necessarily associated. 1103 12

Metal-catalyzed oxidation (MCO) represents a prominent pathway of protein degradation. To evaluate the importance of the integrity of the metal-binding site on MCO, we subjected recombinant human growth hormone (rhGH), to MCO (ascorbate, Cu(2+), (3)O(2)) in the presence of various aliphatic alcohols (ethanol, ethylene glycol, trifluoroethanol, 1-propanol, 2-propanol, 1,2-propylene glycol, 1-butanol, 2-butanol, and tert-butanol). All alcohols inhibited MCO in a concentration-dependent and sigmoidal manner. Half-points, P(1/2), were dependent on the nature of the alcohol. Circular dichroism and fluorescence spectroscopy were used to monitor cosolvent-induced secondary and tertiary structural changes. The presence of alcohols increased the helical content of rhGH and induced a red shift in the tryptophan emission. The midpoints of the tertiary structural change correlated with the P(1/2) values. Solvent polarity at P(1/2) was determined according to the E(T)(30) scale. All alcohol/water mixtures at P(1/2) had rather similar solvent polarities between 54.5 to 56.4 kcal/mol, with the exception of ethylene glycol. On the other hand, no correlation was obtained between the protection against MCO and the hydroxyl radical-scavenging properties of the cosolvent. We conclude that the primary mechanism of MCO inhibition is a cosolvent-induced conformational perturbation of the metal-binding site as opposed to pure radical scavenging.
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PMID:Metal-catalyzed oxidation of human growth hormone: modulation by solvent-induced changes of protein conformation. 1106 79

Riboflavin (RF) is a normal component of the eye lens which triggers a strong photosensitizing activity when exposed to light. Upon irradiation with short wavelength radiations below 400 nm, RF-photosensitized damage may occur. However, vitamin C is present at high concentrations in the normal lens and plays an important role in inhibiting these photosensitization processes. An in vitro simple model was used with the objective of understanding better the relationships between vitamin C and oxygen concentrations on the mechanisms of RF-mediated photodegradation of tryptophan (Trp), a target particularly sensitive to photo-oxidation. Under nitrogen, the RF decomposition reached its maximal value, and vitamin C and Trp photo-oxidation was negligible. When increasing oxygen pressure, RF photodegradation dropped and vitamin C photo-oxidation strongly increased and was maximal at 100% O2. RF-induced photodegradation of Trp first increased with oxygen concentration, up to 40 microM O2, and then decreased. RF and Trp degradation were significantly protected by vitamin C so that no more than 20% of the substrates concentration were oxidized in the presence of vitamin C higher than 0.8 mM. From our results we conclude that in the specific conditions of the normal lens, the high vitamin C concentration (2 mM) is compatible with the UVA radiation hazard, despite the presence of RF. However, if lenticular vitamin C decreases below 0.8 mM, photodegradation of RF may occur and Trp may therefore be photo-oxidized by a Type-I mechanism.
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PMID:Riboflavin photodegradation and photosensitizing effects are highly dependent on oxygen and ascorbate concentrations. 1114 Feb 71

The reactivity of recombinant pea cytosolic ascorbate peroxidase (rAPX) towards H2O2, the nature of the intermediates and the products of the reaction have been examined using UV/visible and EPR spectroscopies together with HPLC. Compound I of rAPX, generated by reaction of rAPX with 1 molar equivalent of H2O2, contains a porphyrin pi-cation radical. This species is unstable and, in the absence of reducing substrate, decays within 60 s to a second species, compound I*, that has a UV/visible spectrum [lambda(max) (nm) = 414, 527, 558 and 350 (sh)] similar, but not identical, to those of both horseradish peroxidase compound II and cytochrome c peroxidase compound I. Small but systematic differences were observed in the UV/visible spectra of compound I* and authentic rAPX compound II, generated by reaction of rAPX with 1 molar equivalent H2O2 in the presence of 1 molar equivalent of ascorbate [lambda(max) (nm) = 416, 527, 554, 350 (sh) and 628 (sh)]. Compound I* decays to give a 'ferric-like' species (lambda(max) = 406 nm) that is not spectroscopically identical to ferric rAPX (lambda(max) = 403 nm) with a first order rate constant, k(decay)' = (2.7 +/- 0.3) x 10(-4) s(-1). Authentic samples of compound II evolve to ferric rAPX [k(decay) = (1.1 +/- 0.2) x 10(-3) s(-1)]. Low temperature (10 K) EPR spectra are consistent with the formation of a protein-based radical, with g values for compound I* (g parallel = 2.038, g perpendicular = 2.008) close to those previously reported for the Trp191 radical in cytochrome c peroxidase (g parallel = 2.037, g perpendicular = 2.005). The EPR spectrum of rAPX compound II was essentially silent in the g = 2 region. Tryptic digestion of the 'ferric-like' rAPX followed by RP-HPLC revealed a fragment with a new absorption peak near 330 nm, consistent with the formation of a hydroxylated tryptophan residue. The results show, for the first time, that rAPX can, under certain conditions, form a protein-based radical analogous to that found in cytochrome c peroxidase. The implications of these data are discussed in the wider context of both APX catalysis and radical formation and stability in haem peroxidases.
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PMID:Detection of a tryptophan radical in the reaction of ascorbate peroxidase with hydrogen peroxide. 1135 29

Myeloperoxidase (MPO), a heme enzyme secreted by activated phagocytes, catalyzes the oxidation of halides to hypohalous acids. At plasma concentrations of halides, hypochlorous acid (HOCl) is the major strong oxidant produced. In contrast, the related enzyme eosinophil peroxidase preferentially generates hypobromous acid (HOBr). Since reagent and MPO-derived HOCl converts low-density lipoprotein (LDL) to a potentially atherogenic form, we investigated the effects of HOBr on LDL modification. Compared to HOCl, HOBr caused 2-3-fold greater oxidation of tryptophan and cysteine residues of the protein moiety (apoB) of LDL and 4-fold greater formation of fatty acid halohydrins from the lipids in LDL. In contrast, HOBr was 2-fold less reactive than HOCl with lysine residues and caused little formation of N-bromamines. Nevertheless, HOBr caused an equivalent increase in the relative electrophoretic mobility of LDL as HOCl, which was not reversed upon subsequent incubation with ascorbate, in contrast to the shift in mobility caused by HOCl. Similar apoB modifications were observed with HOBr generated by MPO/H(2)O(2)/Br(-). In the presence of equivalent concentrations of Cl(-) and Br(-), modifications of LDL by MPO resembled those seen in the presence of Br(-) alone. Interestingly, even at physiological concentrations of the two halides (100 mM Cl(-), 100 microM Br(-)), MPO utilized a portion of the Br(-) to oxidize apoB cysteine residues. MPO also utilized the pseudohalide thiocyanate to oxidize apoB cysteine residues. Our data show that even though HOBr has different reactivities than HOCl with apoB, it is able to alter the charge of LDL, converting it into a potentially atherogenic particle.
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PMID:Comparison of low-density lipoprotein modification by myeloperoxidase-derived hypochlorous and hypobromous acids. 1142 91


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