Enzymatic reduction studies of nitroheterocycles

Viodé, Cécile; Bettache, Nadir; Čėnas, Narimantas; Krauth‐Siegel, R. Luise; Chauvière, G.; Bakalara, Norbert; Périé, Jacques

doi:10.1016/s0006-2952(98)00324-4

Cited by 158 publications

(132 citation statements)

References 49 publications

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“…A number of drugs in current use are believed to mediate part of their activity by inducing oxidative stress either directly by increasing the levels of reactive oxygen species (e.g. nifurtimox) (3,4) or indirectly by affecting the components that mediate the detoxification of reactive oxygen species (e.g. difluoromethylornithine, pentamidine, and trivalent arsenicals) (5)(6)(7)(8).…”

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confidence: 99%

The Trypanosoma cruzi Enzyme TcGPXI Is a Glycosomal Peroxidase and Can Be Linked to Trypanothione Reduction by Glutathione or Tryparedoxin

Wilkinson

Meyer

Taylor

et al. 2002

Journal of Biological Chemistry

131

102

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Trypanosoma cruzi glutathione-dependent peroxidase I (TcGPXI) can reduce fatty acid, phospholipid, and short chain organic hydroperoxides utilizing a novel redox cycle in which enzyme activity is linked to the reduction of trypanothione, a parasite-specific thiol, by glutathione. Here we show that TcGPXI activity can also be linked to trypanothione reduction by an alternative pathway involving the thioredoxin-like protein tryparedoxin. The presence of this new pathway was first detected using dialyzed soluble fractions of parasite extract. Tryparedoxin was identified as the intermediate molecule following purification, sequence analysis, antibody studies, and reconstitution of the redox cycle in vitro. The system can be readily saturated by trypanothione, the rate-limiting step being the interaction of trypanothione with the tryparedoxin. Both tryparedoxin and TcGPXI operate by a ping-pong mechanism. Overexpression of TcGPXI in transfected parasites confers increased resistance to exogenous hydroperoxides. TcGPXI contains a carboxyl-terminal tripeptide (ARI) that could act as a targeting signal for the glycosome, a kinetoplastid-specific organelle. Using immunofluorescence, tagged fluorescent proteins, and biochemical fractionation, we have demonstrated that TcGPXI is localized to both the glycosome and the cytosol. The ability of TcGPXI to use alternative electron donors may reflect their availability at the corresponding subcellular sites.

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The Trypanosoma cruzi Enzyme TcGPXI Is a Glycosomal Peroxidase and Can Be Linked to Trypanothione Reduction by Glutathione or Tryparedoxin

Wilkinson

Meyer

Taylor

et al. 2002

Journal of Biological Chemistry

131

102

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“…14 De acordo com dados da literatura é consenso que o mecanismo de ação desta classe de compostos está ligado ao processo de redução in vivo do grupo nitro e à subseqüente interação dos produtos formados, a partir desta reação, com biomoléculas essenciais de bactérias, fungos e parasitas. 16,17,52,53 A ativação biológica através do processo de biorredução de nitrocompostos apresenta-se como alvo para o aperfeiçoamento da atividade biológica desta classe de compostos. Assim, Rozenski e colaboradores, em 1995, conseguiram relacionar a ação antibacteriana com o potencial de redução de alguns nitrocompostos, comprovando que esta bioatividade é decorrente da redução do grupo nitro.…”

Section: Mecanismo De Açãounclassified

“…•+ e a inativação enzimática desempenhada pelo 14,16,17,53 Assim, de acordo com a Figura 3, verifica-se que o processo de redução depende da estrutura do nitrocomposto e do meio onde ocorre. Neste processo, existem evidências que a recepção de 1 elétron a partir do primeiro passo de redução do grupo nitro, demonstrado pelo par Ar-NO 2 /Ar-NO 2…”

Section: Mecanismo De Açãounclassified

“…14,16,17 Com relação à atividade antibacteriana, do mesmo modo como descrito para alguns parasitas, alguns compostos nitro-heterocíclicos são metabolizados por redutases ligadas à ferrodoxina (fotobactérias) e pelo complexo piruvato (flavoproteínas NAD(P)H e ferrodoxinas) de alguns microrganismos com comportamento aeróbio ou anaeró-bio.…”

Section: Mecanismo De Açãounclassified

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Aspectos mecanísticos da bioatividade e toxicidade de nitrocompostos

Paulai¹,

Serrano²,

Tavares³

2009

Quím. Nova

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“…Their activity is due at least in part to the welldocumented sensitivity of trypanosomes and particularly T. cruzi towards oxidative stress. Upon one electron reduction these compounds generate radical anions (R-NO 2 / R-NO 2 • ), which interfere with oxygen metabolism (LaScalea 1998, Viodé et al 1999). For Benznidazole, the generation of reduced reactive species that react with parasite macromolecules is also proposed (Urbina 1999).…”

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confidence: 99%