Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P47989 (xanthine oxidase)
 8,633 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The poly(ADP-ribosylation) of chromosomal proteins is an epigenetic consequence of clastogenic DNA damaging agents which affects chromatin structure and function. We studied the poly(ADP-ribosylation) of the major classes of histones in response to DNA breakage induced by an extracellular burst of active oxygen (AO) or the alkylating agent N-methyl-N'-nitrosoguandine (MNNG) in the immortalized human keratinocytes HaCa T using a combination of affinity chromatography on phenylboronate resin and immunoblotting with polyclonal antibodies against histones H1, H2B, H2A, H3, and H4. The following findings characterized the poly(ADPR) reaction: (1) pretreatment of nuclear extracts with snake venom phosphodiesterase which removes poly(ADPR) chains strongly reduced the material which was retained by phenylboronate; (2) the ADPR transferase inhibitor benzamide (100 microM) suppressed AO-induced poly(ADP-ribosylation); (3) poly(ADP-ribosylation) reduced the electrophoretic mobility of the modified histones. Several histones were constitutively poly(ADP-ribosylated) in untreated controls: 0.03% of H2A, 0.04-0.06% of H2B, and 0.04% of H3.1 carried at least one poly(ADPR) chain of undetermined length. AO transiently increased the poly(ADPR) levels of all major histones with the exception of H1. The extent of substitution 30 min after exposure to AO generated by 50 micrograms/mL xanthine and 5 micrograms/mL xanthine oxidase was 0.8% for A24 greater than 0.3% for H4 greater than 0.1% for H3.1 = 0.1% for H3.2 = 0.1% for H2B.2 greater than 0.09% for H2A. Within 60 min, poly(ADPR) substitution had decreased to control levels for H3 and H4 and below control levels for H2A and H2B.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Poly(ADP-ribosylation) of histones in intact human keratinocytes. 247 78

Porfiromycin was reductively metabolized by NADPH cytochrome P-450 reductase and xanthine oxidase under anaerobic conditions. The production of metabolites varied with the pH and the contents of the reaction buffer. In Tris buffer, two major metabolites were produced at pH 7.5 and above, whereas one major metabolite was produced at pH 6.5. The three major metabolites were separated and isolated by HPLC. Identification by californium-252 plasma desorption mass spectrometry showed that the two major metabolites from pH 7.5 were (trans) and (cis)-forms of 7-amino-1-hydroxyl-2-methylaminomitosene and the major metabolite from pH 6.5 was 7-amino-2-methylaminomitosene. All three major metabolites showed substitutions at the C-1 position. DNA was alkylated readily by enzyme-activated porfiromycin. Digestion of porfiromycin-alkylated DNA by DNase, snake venom phosphodiesterase, and alkaline phosphatase resulted in an insoluble nuclease-resistant fraction and a soluble fraction. The nuclease-resistant fraction reflected a high content of cross-linked adducts. Upon HPLC analysis, the solubilized fraction contained two monofunctionally linked porfiromycin adducts and a possibly cross-linked dinucleotide. The major adduct was isolated by HPLC and identified by NMR, as N2-(2'-deoxyguanosyl)-7-amino-2-methylaminomitosene. The N2 position of deoxyguanosine appeared as the major monofunctional alkylating site for DNA alkylation by porfiromycin. Thus, mitomycin C and porfiromycin (which differs from mitomycin C only by the addition of a methyl group to the aziridine nitrogen) share the same enzymatic activating mechanism that leads to the formation of the same types of metabolites and the same specificity of DNA alkylation.
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PMID:Metabolites and DNA adduct formation from flavoenzyme-activated porfiromycin. 341 25