Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:1.17.1.4 (xanthine dehydrogenase)
 1,236 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Retinal oxidase (retinoic acid synthase) (EC 1.2.3.11) was purified electrophoretically, as a single protein band, from rabbit liver cytosol. The characteristic properties, enzymatic reaction mechanism, substrate specificity and kinetic parameters for retinals and molecular oxygen of the retinal oxidase were investigated. The Km values for all-trans-retinal of the retinal oxidase was the lowest than those for the other retinal derivatives. The retinal oxidase is a metalloflavoenzyme containing 2 FADs as the coenzyme, and 8 irons, 2 molybdenums, 2 disulfide bonds and 8 inorganic sulfurs. Its relative molecular mass was determined to be 270 kDa by gel filtration HPLC on a TSKgel G3000swXL column. Its minimum molecular mass was estimated to be 135 kDa by SDS-PAGE. The optical spectrum of the retinal oxidase showed absorption peaks at 275, 340 and 450 nm, and shoulders at 420 and 473 nm, in the oxidized form. The molecular extinction coefficients of the oxidase at selected wavelengths were determined. Circular dichroism spectra of the retinal oxidase were measured in the ultraviolet and visible regions. These spectra showed positive absorption in the visible region. The amino-acid composition was determined. The activity of the oxidase was not affected by any cofactors, such as NADP+, NAD+, NADPH and NADH, and it did not occur under anaerobic conditions. The oxidase was not inhibited by BOF-4272, a potent inhibitor of xanthine dehydrogenase, or rat anti-xanthine dehydrogenase IgG. Experiments on retinoic acid formation under 18O2 or H2(18)O demonstrated that the oxygen of water was incorporated into retinoic acid by the retinal oxidase, but not molecular oxygen.
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PMID:Characteristic properties of retinal oxidase (retinoic acid synthase) from rabbit hepatocytes. 830 67

The IMP dehydrogenase inhibitor, tiazofurin (TR)-2-beta-D-ribofuranosylthiazole-4-carboxamide, which exhibited oncolytic activity in patients with chronic myelogenous leukaemia (CML) in blast crisis was found to inhibit the growth of human neuroblastoma SK-N-SH cells with an IC50 of 4.2 microM. TR treatment of cells perturbed nucleic acid and catecholamine pathways. As biochemical markers of TR action decreased cellular GTP pools, increased inosine and hypoxanthine concentrations and depleted dopamine content were found. Incubation of tumour specimens obtained from paediatric patients with grade-IV neuroblastoma with TR resulted in the formation of the active metabolite, thiazole-4-carboxamide adenine dinucleotide, in concentrations sufficient to inhibit tumour growth. Cytotoxic and biochemical effects of TR were enhanced by combining it with allopurinol (an inhibitor of xanthine dehydrogenase), and hypoxanthine (an alternate substrate for hypoxanthine-guanine phosphoribosyltransferase). Induction of transdifferentiation of SK-N-SH cells from a neuroblast to an epitheloid, substrate-adherent phenotype was more pronounced with TR than with all-trans-retinoic acid. Transdifferentiating treatment with TR resulted in a 2-fold-enhanced sensitivity towards adriamycin. However, differentiation with all-trans-retinoic acid rendered the cells more resistant to adriamycin. Our results suggest that TR might be a promising agent for the treatment of children suffering from neuroblastoma.
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PMID:Cytotoxicity, differentiating activity and metabolism of tiazofurin in human neuroblastoma cells. 834 56

Retinoic acid is considered to be the active metabolite of retinol, able to control differentiation and proliferation of epithelia. Retinoic acid biosynthesis has been widely described with the implication of multiple enzymatic activities. However, our understanding of the cell biological function and regulation of this process is limited. In a recent study we evidenced that milk xanthine oxidase (E.C. 1.17.3.2.) is capable to oxidize all-trans-retinol bound to CRBP (holo-CRBP) to all-trans-retinaldehyde and then to all-trans-retinoic acid. To get further knowledge regarding this process we have evaluated the biosynthetic pathway of retinoic acid in a human mammary epithelial cell line (HMEC) in which xanthine dehydrogenase (E.C. 1.17.1.4.), the native form of xanthine oxidase, is expressed. Here we report the demonstration of a novel retinol oxidation pathway that in the HMEC cytoplasm directly conduces to retinoic acid. After isolation and immunoassay of the cytosolic protein showing retinol oxidizing activity we identified it with the well-known enzyme xanthine dehydrogenase. The NAD+ dependent retinol oxidation catalyzed by xanthine dehydrogenase is strictly dependent on cellular retinol binding proteins and is inhibited by oxypurinol. In this work, a new insight into the biological role of xanthine dehydrogenase is given.
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PMID:Xanthine dehydrogenase processes retinol to retinoic acid in human mammary epithelial cells. 1856 34

The seeming impairment of retinoid metabolism in human breast tumor cells has been attributed to the lower expression of cellular retinol binding proteins (CRBPs), of alcohol/retinol dehydrogenases, or aldehyde/retinaldehyde dehydrogenases. In a previous study we indicated that xanthine dehydrogenase (XDH) is able to oxidize actively both all-trans-retinol (t-ROL) bound to the CRBP (holo-CRBP) and all-trans-retinaldehyde (t-RAL) to all-trans-retinoic acid (t-RA) in human mammary epithelial cells (HMEC). Since both XDH and CRBP are required for the biosynthesis of t-RA, we have inspected their bioavailability in both estrogen-responsive and nonresponsive human mammary epithelial cancer cells. The XDH activity, as assessed in the crude and purified extracts of both MCF7 and MDA-MB 231 cells by measuring the substrate t-RAL (that unlike t-ROL does not need CRBP), was 6 to 10 times lower than that previously encountered in normal HMEC. In addition, CRBP expression was absent in either cell line. Based on this preliminary evidence, we propose here that the low levels of XDH activity and the associated absence of CRBP in both MCF7 and MDA-MB 231 human breast cancer cells might be responsible for the retinoic acid deficiency observed in these cell model systems. This defect may be the crux of the impairment to stem cell differentiation and, hence, may be primarily implicated in human mammary carcinogenesis.
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PMID:Low levels of both xanthine dehydrogenase and cellular retinol binding protein are responsible for retinoic acid deficiency in malignant human mammary epithelial cells. 1925 Feb 15

We previously reported that the all-cis isomer of arachidonic acid, the most naturally occurring isoform of this fatty acid, reduced cuprous copper ion-induced conversion of xanthine dehydrogenase into its reactive oxygen species generating form, xanthine oxidase. In the present study, the effects of all-trans isomer of arachidonic acid, in comparison with cis isomer of arachidonic acid, on the xanthine dehydrogenase/xanthine oxidase interconversion were explored. cis isomer of arachidonic acid alone did not have any significant effect on the activities of xanthine dehydrogenase and xanthine oxidase, but it inhibited the cuprous copper ion-induced conversion of xanthine dehydrogenase to xanthine oxidase in rat liver cytosol in vitro. In contrast, trans isomer of arachidonic acid elicited an increase in xanthine oxidase activity concomitant with a decrease in xanthine dehydrogenase activity, and further potentiated the cuprous copper ion-induced xanthine dehydrogenase/xanthine oxidase interconversion. In primary rat hepatocyte cultures, trans isomer of arachidonic acid increased 2',7'-dichlorofluorescein-fluorescence intensity in the cytosolic fraction from 2',7'-dichlorodihydrofluorescein, an indicator of reactive oxygen species generation. The pretreatment of allopurinol, an xanthine oxidase inhibitor, diminished the trans isomer of arachidonic acid-induced increase in the 2',7'-dichlorofluorescein-fluorescence intensity, indicating the role of xanthine dehydrogenase/xanthine oxidase in mediating trans isomer of arachidonic acid-induced reactive oxygen species generation. These observations suggest that, in contrast to all-cis arachidonic acid, all-trans arachidonic acid has the potential to enhance reactive oxygen species generation via xanthine dehydrogenase/xanthine oxidase interconversion in the liver cytosol in vitro.
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PMID:All-trans Arachidonic acid generates reactive oxygen species via xanthine dehydrogenase/xanthine oxidase interconversion in the rat liver cytosol in vitro. 2279 14