The dual face of endogenous α-aminoketones: Pro-oxidizing metabolic weapons

Bechara, Etelvino J.H.; Dutra, Fernando; Cardoso, V. E. S.; Sartori, Adriano; Olympio, Kelly Polido Kaneshiro; Penatti, Carlos A. A.; Adhikari, Avishek; Assunção, Nilson Antônio

doi:10.1016/j.cbpc.2006.07.004

Cited by 49 publications

(63 citation statements)

References 224 publications

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“…As a precursor of heme biosynthesis, ALA is an essential compound for E. coli cell growth. An increase in intracellular ALA concentration was, however, shown to be harmful to the E. coli cells, because ALA induces oxidative stress in the presence of ferric ions (4,11,28). Thus, the effect of the fur mutation, which causes the increased uptake of iron ions, on the ALA sensitivity of the E. coli cells was examined.…”

Section: Resultsmentioning

confidence: 99%

“…On the other hand, extracellular ALA is incorporated into the cells via the dipeptide transporter system (43). Although ALA is a heme precursor, increased intracellular ALA concentrations cause oxidative stress in the presence of Fe 2ϩ ions (4,11,28). Since ALA-induced reactive oxygen acts on the guanine base of DNA, ALA can be a mutagenic compound.…”

Section: Discussionmentioning

confidence: 99%

“…In E. coli, ALA is formed from glutamyl-tRNA by the action of glutamyl-tRNA reductase, which is encoded by hemA, and glutamate-1-semialdehyde aminotransferase, which is encoded by hemL (2,13). ALA is an essential precursor for heme biosynthesis; however, increased concentrations of it induce oxidative stress in the presence of Fe 2ϩ ions (4,11,28). The second step of heme biosynthesis is catalyzed by porphobilinogen synthase, which is encoded by hemB (18).…”

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confidence: 99%

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TolC-Dependent Exclusion of Porphyrins in Escherichia coli

Tatsumi

Wachi

2008

J Bacteriol

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We found that Escherichia coli tolC mutants showed increased sensitivity to 5-aminolevulinic acid (ALA), a precursor of porphyrins. The tolC mutant cells grown in the presence of ALA showed a reddish brown color under visible light and a strong red fluorescence under near-UV irradiation. Fluorescence spectrometry and high-performance liquid chromatography analysis showed that the tolC mutant cells grown in the presence of ALA accumulated a large amount of coproporphyrin(ogen) intracellularly. In contrast, the wild-type cells produced coproporphyrin extracellularly. The tolC mutant cells grown in the presence of ALA, which were capable of surviving in the dark, were killed by near-UV irradiation, suggesting that the intracellular coproporphyrin(ogen) renders these cells photosensitive. These results suggest that the TolC-dependent efflux system is involved in the exclusion of porphyrin(ogen)s in E. coli.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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TolC-Dependent Exclusion of Porphyrins in Escherichia coli

Tatsumi

Wachi

2008

J Bacteriol

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“…Bechara and co-workers 48 have reported that the accumulation of ALA affects the aerobic metabolism and has some pro-oxidant activity. In this context, we assume that the toxicological effects caused by diphenyl diselenide probably involve the accumulation of ALA, which produces reactive oxygen species, and the impairment of heme biosynthesis pathway as a consequence of δ-ALA-D inhibition (Figure 7).…”

Section: Functional Consequences Of D-ala-d Inhibitionmentioning

confidence: 99%

Diphenyl diselenide a janus-faced molecule

Nogueira

Rocha

2010

J. Braz. Chem. Soc.

198

105

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Este artigo de revisão aborda uma reflexão sobre o potencial terapêutico ou tóxico de compostos orgânicos de selênio, dando particular ênfase ao disseleneto de difenila e alguns dos seus análogos estruturais. Algumas características moleculares relacionadas com a toxicidade e farmacologia do disseleneto de difenila in vitro e in vivo são abordadas. Os artigos revisados, que abordam experimentos in vivo, indicam que a interação do disseleneto de difenila com tióis pode determinar seu potencial farmacológico ou toxicológico. Além disso, uma limitada ativação da rota de toxicidade, isto é, a oxidação controlada de moléculas de alto peso molecular, que contém grupos tióis, poderia contribuir para os efeitos farmacológicos do disseleneto de difenila. Concluise que a síntese de compostos orgânicos de selênio deve ser direcionada para o desenvolvimento de novos disselenetos de diorganoila que possam interagir com alvos moleculares específicos.In this review, we summarized the potential role of synthetic organoseleno compounds as therapeutic or toxic agents, giving emphasis almost exclusively to diphenyl diselenide, the simplest of the diaryl diselenides, and some of its analogs. We presented the main molecular aspects related to the in vitro toxicity and pharmacology of diphenyl diselenide and also provided in vivo data indicating that the interaction of diphenyl diselenide with thiols can dictate either its toxicological or pharmacological property. The papers covered in this review indicate that a limited activation of the "toxic pathway", i.e., a controlled oxidation of specific high molecular weight thiol-containing molecules could contribute to the pharmacological effects of diphenyl diselenide. In conclusion, this review reinforces the necessity of developing new diorganoyl diselenides that could interact with specific molecular targets.

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“…AA is also associated with a variety of injuries in biomolecules and with mitochondrial and cell dysfunction and apoptosis [14], [19]–[20]. Among other α-aminoketones of biological interest that can produce reactive α-oxoaldehydes and ROS by aerobic oxidation, we mention 5-aminolevulinic acid (ALA) [21], a heme precursor accumulated in porphyric disorders, and 1,4-diaminobutanone (DAB), a wide spectrum microbicide [22], [23].…”

Section: Introductionmentioning

confidence: 99%

Ferricytochrome c Directly Oxidizes Aminoacetone to Methylglyoxal, a Catabolite Accumulated in Carbonyl Stress

et al. 2013

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Age-related diseases are associated with increased production of reactive oxygen and carbonyl species such as methylglyoxal. Aminoacetone, a putative threonine catabolite, is reportedly known to undergo metal-catalyzed oxidation to methylglyoxal, NH4 + ion, and H2O2 coupled with (i) permeabilization of rat liver mitochondria, and (ii) apoptosis of insulin-producing cells. Oxidation of aminoacetone to methylglyoxal is now shown to be accelerated by ferricytochrome c, a reaction initiated by one-electron reduction of ferricytochrome c by aminoacetone without amino acid modifications. The participation of O2 •− and HO• radical intermediates is demonstrated by the inhibitory effect of added superoxide dismutase and Electron Paramagnetic Resonance spin-trapping experiments with 5,5′-dimethyl-1-pyrroline-N-oxide. We hypothesize that two consecutive one-electron transfers from aminoacetone (E0 values = −0.51 and −1.0 V) to ferricytochrome c (E0 = 0.26 V) may lead to aminoacetone enoyl radical and, subsequently, imine aminoacetone, whose hydrolysis yields methylglyoxal and NH4 + ion. In the presence of oxygen, aminoacetone enoyl and O2 •− radicals propagate aminoacetone oxidation to methylglyoxal and H2O2. These data endorse the hypothesis that aminoacetone, putatively accumulated in diabetes, may directly reduce ferricyt c yielding methylglyoxal and free radicals, thereby triggering redox imbalance and adverse mitochondrial responses.

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The dual face of endogenous α-aminoketones: Pro-oxidizing metabolic weapons

Cited by 49 publications

References 224 publications

TolC-Dependent Exclusion of Porphyrins in Escherichia coli

TolC-Dependent Exclusion of Porphyrins in Escherichia coli

Diphenyl diselenide a janus-faced molecule

Ferricytochrome c Directly Oxidizes Aminoacetone to Methylglyoxal, a Catabolite Accumulated in Carbonyl Stress

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