Studies on Metalloflavoproteins. IV. The Role of the Metal1

Mahler, H. R.; Fairhurst, Alan S.; Mackler, Bruce

doi:10.1021/ja01611a035

Cited by 72 publications

(16 citation statements)

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“…The Michaelis constant, Ks, obtained for xanthine dehydrogenase of Drosophila was 5 x 10-5M. This value is in good agreement with that of xanthine oxidase reported by Mackler et al (1954). From the result shown in Figure 6, it seems that DPNH is a competitive inhibitor against xanthine for the xanthine oxidation by the xanthine dehydrogenase from Drosophila in the presence of methylene blue as the hydrogen acceptor.…”

Section: Purine Contents In Oregon-r and Ry Mutant Strainssupporting

confidence: 88%

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BIOCHEMICAL GENETICS OF PURINE CATABOLISM IN DROSOPHILA MELANOGASTER

Morita

1964

The Japanese journal of genetics

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Section: Purine Contents In Oregon-r and Ry Mutant Strainssupporting

confidence: 88%

“…Conclusive evidence is presented to support the suggestion of Mackler et al (1954) that the enzyme involved in xanthine oxidation also has the capacity of DPNH oxidation.…”

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confidence: 54%

BIOCHEMICAL GENETICS OF PURINE CATABOLISM IN DROSOPHILA MELANOGASTER

Morita

1964

The Japanese journal of genetics

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“…Co-incubation of menadione, in the absence of allopurinol, resulted in the stimulation of metabolism for each substrate (32). This phenomenon of XO stimulation by menadione was first observed by Mahler et al (39), continues to appear in the literature (35,36,40), and is seen in the metabolism of M 1 dG (32). Stimulation by menadione was mitigated when saturating concentrations of allopurinol were used.…”

Section: Discussionmentioning

confidence: 83%

Metabolism in Vitro and in Vivo of the DNA Base Adduct, M₁G

Knutson

Akingbade

Crews

et al. 2007

Chem. Res. Toxicol.

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Oxidative damage is considered a major contributing factor to genetic diseases including cancer. Our laboratory is evaluating endogenously formed DNA adducts as genomic biomarkers of oxidative injury. Recent efforts have focused on investigating the metabolic stability of adducts in vitro and in vivo. Here, we demonstrate that the base adduct, M 1 G, undergoes oxidative metabolism in vitro in rat liver cytosol (RLC, K m ) 105 µM and V max /K m ) 0.005 min -1 mg -1 ) and in vivo when administered intravenously to male Sprague Dawley rats. LC-MS analysis revealed two metabolites containing successive additions of 16 amu. One-and two-dimensional NMR experiments showed that oxidation occurred first at the 6-position of the pyrimido ring, forming 6-oxo-M 1 G, and then at the 2-position of the imidazole ring, yielding 2,6-dioxo-M 1 G. Authentic 6-oxo-M 1 G was chemically synthesized and observed to undergo metabolism to 2,6-dioxo-M 1 G in RLC (K m ) 210 µM and V max /K m ) 0.005 min -1 mg -1 ). Allopurinol partially inhibited M 1 G metabolism (75%) and completely inhibited 6-oxo-M 1 G metabolism in RLC. These inhibition studies suggest that xanthine oxidase is the principal enzyme acting on M 1 G in RLC and the only enzyme that converts 6-oxo-M 1 G to 2,6-dioxo-M 1 G. Both M 1 G and 6-oxo-M 1 G are better substrates (5-fold) for oxidative metabolism in RLC than the deoxynucleoside, M 1 dG. Alternative repair pathways or biological processing of M 1 dG makes the fate of M 1 G of interest as a potential marker of oxidative damage in vivo.

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“…In reference to the vehicle control, M 1 dG metabolism was inhibited by allopurinol (7%) and stimulated by menadione (195%). Menadione and other quinones can be reduced by flavoproteins such as xanthine oxidase during the oxidation of reducing substrates (22), thereby stimulating oxidation (23,24). Thus, preliminary in vitro data implicate xanthine oxidase in the oxidation of M 1 dG in rat liver cytosol.…”

Section: Resultsmentioning

confidence: 93%

In vivo oxidative metabolism of a major peroxidation-derived DNA adduct, M ₁ dG

Otteneder¹,

Knutson²,

Daniels³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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3-(2-Deoxy-␤-D-erythro-pentofuranosyl)pyrimido[1,2-␣]purin-10(3H)-one (M1dG) is a DNA adduct arising from the reaction of 2-deoxyguanosine with the lipid peroxidation product, malondialdehyde, or the DNA peroxidation product, base propenal. M 1dG is mutagenic in bacteria and mammalian cells and is present in the genomic DNA of healthy human beings. It is also detectable, albeit at low levels, in the urine of healthy individuals, which may make it a useful biomarker of DNA damage linked to oxidative stress. We investigated the possibility that the low urinary levels of M 1dG reflect metabolic conversion to derivatives. M 1dG was rapidly removed from plasma (t1/2 ‫؍‬ 10 min) after i.v. administration to rats. A single urinary metabolite was detected that was identified as 6-oxo-M 1dG by MS, NMR spectroscopy, and independent chemical synthesis. 6-Oxo-M1dG was generated in vitro by incubation of M 1dG with rat liver cytosols, and studies with inhibitors suggested that xanthine oxidase and aldehyde oxidase are involved in the oxidative metabolism. M1dG also was metabolized by three separate human liver cytosol preparations, indicating 6-oxo-M1dG is a likely metabolite in humans. This represents a report of the oxidative metabolism of an endogenous DNA adduct and raises the possibility that other endogenous DNA adducts are metabolized by oxidative pathways. 6-Oxo-M1dG may be a useful biomarker of endogenous DNA damage associated with inflammation, oxidative stress, and certain types of cancer chemotherapy.excretion ͉ inflammation ͉ DNA damage ͉ oxidation ͉ metabolite D NA damage from endogenous sources is believed to contribute significantly to human genetic diseases, including cancer (1, 2). A major cause of endogenous DNA damage is oxidation (3, 4). Agents such as hydroxyl radical or peroxynitrous acid oxidize nucleic acid bases or the deoxyribose backbone to form miscoding lesions or induce strand breaks (5). In addition, oxidation of other cellular constituents (i.e., lipid, protein) generates reactive derivatives that form adducts with nucleic acid bases (1). In the absence of repair, this panoply of damage results in mutations, triggers signaling to arrest cell division, or induces apoptosis.3-(2-Deoxy-␤-D-er ythro-pentofuranosyl)pyrimido[1,2-␣]purin-10(3H)-one (M 1 dG) is an adduct found at varying levels in genomic DNA of rodents and humans (6-8). It is derived from the lipid oxidation product, malondialdehyde, or the DNA oxidation product, base propenal (Scheme 1) (9-11). M 1 dG is miscoding when assayed by in vitro DNA replication and is mutagenic in bacterial and mammalian cells (12)(13)(14). It induces base pair substitutions (M 1 dG3T and M 1 dG3A) and frameshift mutations in reiterated sequences (e.g., CG n ) when shuttle vectors containing a site-specific lesion are replicated in COS-7 cells (14). Genetic and biochemical experiments indicate that M 1 dG is removed by nucleotide excision repair in both bacterial and mammalian cells (13-15).As a prerequisite for preclinical, clinical, and populationbased ...

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Studies on Metalloflavoproteins. IV. The Role of the Metal¹

Cited by 72 publications

References 0 publications

BIOCHEMICAL GENETICS OF PURINE CATABOLISM IN <i>DROSOPHILA MELANOGASTER</i>

BIOCHEMICAL GENETICS OF PURINE CATABOLISM IN <i>DROSOPHILA MELANOGASTER</i>

Metabolism in Vitro and in Vivo of the DNA Base Adduct, M₁G

In vivo oxidative metabolism of a major peroxidation-derived DNA adduct, M ₁ dG

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Studies on Metalloflavoproteins. IV. The Role of the Metal1

Cited by 72 publications

References 0 publications

BIOCHEMICAL GENETICS OF PURINE CATABOLISM IN <i>DROSOPHILA MELANOGASTER</i>

BIOCHEMICAL GENETICS OF PURINE CATABOLISM IN <i>DROSOPHILA MELANOGASTER</i>

Metabolism in Vitro and in Vivo of the DNA Base Adduct, M1G

In vivo oxidative metabolism of a major peroxidation-derived DNA adduct, M 1 dG

Contact Info

Product

Resources

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Studies on Metalloflavoproteins. IV. The Role of the Metal¹

Metabolism in Vitro and in Vivo of the DNA Base Adduct, M₁G

In vivo oxidative metabolism of a major peroxidation-derived DNA adduct, M ₁ dG