Oxidative DNA Damage Induced by Aminoacetone, an Amino Acid Metabolite

Hiraku, Yusuke; Sugimoto, Junko; Yamaguchi, Tadatoshi; Kawanishi, Shosuke

doi:10.1006/abbi.1999.1161

Cited by 30 publications

(20 citation statements)

References 45 publications

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“…In addition to the reported SSAO-independent DNA damage, [62] the current findings of changes in ferritin and apoferritin may contribute to explaining intracellular iron-induced oxidative stress during AA accumulation in diabetes mellitus patients. …”

Section: Resultsmentioning

confidence: 62%

Aminoacetone Induces Loss of Ferritin Ferroxidase and Iron Uptake Activities

Dutra

Araki

Bechara

2003

Free Radical Research

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Aminoacetone (AA) is a threonine and glycine metabolite overproduced and recently implicated as a contributing source of methylglyoxal (MG) in conditions of ketosis. Oxidation of AA to MG, NH4+, and H2O2 has been reported to be catalyzed by a copper-dependent semicarbazide sensitive amine oxidase (SSAO) as well as by copper- and iron ion-catalyzed reactions with oxygen. We previously demonstrated that AA-generated O2*-. and enoyl radical (AA*) induce dose-dependent Fe(II) release from horse spleen ferritin (HoSF); no reaction occurs under nitrogen. In the present study we further explored the mechanism of iron release and the effect of AA on the ferritin apoprotein. Iron chelators such as EDTA, ATP and citrate, and phosphate accelerated AA-promoted iron release from HoSF, which was faster in horse spleen isoferritins containing larger amounts of phosphate in the core. Incubation of apoferritin with AA (2.5-50 mM, after 6 h) changes the apoprotein electrophoretic behavior, suggesting a structural modification of the apoprotein by AA-generated ROS. Superoxide dismutase (SOD) was able to partially protect apoferritin from structural modification whereas catalase, ethanol, and mannitol were ineffective in protection. Incubation of apoferritin with AA (1-10 mM) produced a dose-dependent decrease in tryptophan fluorescence (13-30%, after 5 h), and a partial depletion of protein thiols (29% after 24 h). The AA promoted damage to apoferritin produced a 40% decrease in apoprotein ferroxidase activity and an 80% decrease in its iron uptake ability. The current findings of changes in ferritin and apoferritin may contribute to intracellular iron-induced oxidative stress during AA formation in ketosis and diabetes mellitus.

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Section: Resultsmentioning

confidence: 62%

Aminoacetone Induces Loss of Ferritin Ferroxidase and Iron Uptake Activities

Dutra

Araki

Bechara

2003

Free Radical Research

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“…Copper ions released to the medium by oxidativemodified CP may catalyze AA aerobic oxidation (31). Accordingly, the presence of CP was shown to triple the rate of oxygen consumption by AA (Figure 4).…”

Section: Resultsmentioning

confidence: 98%

Aminoacetone Induces Oxidative Modification to Human Plasma Ceruloplasmin

Dutra

Ciriolo

Calabrese

et al. 2005

Chem. Res. Toxicol.

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Aminoacetone (AA), a putative endogenous source of cytotoxic methylglyoxal, and ceruloplasmin (CP), the antioxidant plasma copper transporter, are known to increase in diabetes. AA was recently shown in vitro to act as a pro-oxidant toward ferritin and isolated mitochondria. We now report AA oxidative effects on CP mediated by AA-generated reactive oxygen species (ROS). Incubation of 1.5 microM human CP with 0.05-1 mM AA resulted in extensive protein aggregation. That ROS-driven thiol cross-linking underlies the CP aggregation was evidenced by the inhibitory effects of added superoxide dismutase, catalase, mannitol, and dithiothreitol. The addition of CP to AA (mM) solutions accelerated oxygen consumption by AA and caused CP copper ion release and loss of ferroxidase and aminoxidase activities. If operative in vivo, this reaction would impair the antioxidant role of CP and iron uptake by ferritin and hence contribute to intracellular iron-induced oxidative stress during AA accumulation in diabetes mellitus.

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“…It was found that aminoacetone reduced the growth of Δaao So -mutT mutant by 11%, but it increased the growth of the wild-type and Δaao So mutant by 10% (Table 3). Cellular aminoacetone can be derived from threonine or glycine [24], so we supplied threonine to the mutant cultures. Effects of threonine on growth were similar to those of aminoacetone (data not shown).…”

Section: Resultsmentioning

confidence: 99%

“…Pronounced aminoacetone oxidase activity was detected for LAAO, although it was first identified as an amino acid oxidase [11]. Cellular aminoacetone can be derived either from threonine or a condensation of glycine and acetyl-CoA [24], [27]. Threonine dehydrogenase, a key enzyme in L-threonine metabolism, catalyzes the conversion of L-threonine to 2-amino-3-ketobutyrate, and the latter is spontaneously decarboxylated to aminoacetone [28].…”

Section: Discussionmentioning

confidence: 99%

Role of Operon aaoSo-mutT in Antioxidant Defense in Streptococcus oligofermentans

et al. 2012

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Previously, we have found that an insertional inactivation of aaoSo, a gene encoding L-amino acid oxidase (LAAO), causes marked repression of the growth of Streptococcus oligofermentans. Here, we found that aaoSo and mutT, a homolog of pyrophosphohydrolase gene of Escherichia coli, constituted an operon. Deletion of either gene did not impair the growth of S. oligofermentans, but double deletion of both aaoSo and mutT was lethal. Quantitative PCR showed that the transcript abundance of mutT was reduced for 13-fold in the aaoSo insertional mutant, indicating that gene polarity derived from the inactivation of aaoSo attenuated the expression of mutT. Enzymatic assays were conducted to determine the biochemical functions of LAAO and MutT of S. oligofermentans. The results indicated that LAAO functioned as an aminoacetone oxidase [47.75 nmol H2O2 (min·mg protein)–1]; and MutT showed the pyrophosphohydrolase activity, which removed mutagens such as 8-oxo-dGTP. Like paraquat, aaoSo mutations increased the expression of SOD, and addition of aminoacetone (final concentration, 5 mM) decreased the mutant’s growth by 11%, indicating that the aaoSo mutants are under ROS stress. HPLC did reveal elevated levels of cytoplasmic aminoacetone in both the deletion and insertional gene mutants of aaoSo. Electron spin resonance spectroscopy showed increased hydroxyl radicals in both types of aaoSo mutant. This demonstrated that inactivation of aaoSo caused the elevation of the prooxidant aminoacetone, resulting the cellular ROS stress. Our study indicates that the presence of both LAAO and MutT can prevent endogenous metabolites-generated ROS and mutagens. In this way, we were able to determine the role of the aaoSo-mutT operon in antioxidant defense in S. oligofermentans.

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Oxidative DNA Damage Induced by Aminoacetone, an Amino Acid Metabolite

Cited by 30 publications

References 45 publications

Aminoacetone Induces Loss of Ferritin Ferroxidase and Iron Uptake Activities

Aminoacetone Induces Loss of Ferritin Ferroxidase and Iron Uptake Activities

Aminoacetone Induces Oxidative Modification to Human Plasma Ceruloplasmin

Role of Operon aaoSo-mutT in Antioxidant Defense in Streptococcus oligofermentans

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