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1.
Essays Biochem ; 68(1): 27-39, 2024 Apr 30.
Artículo en Inglés | MEDLINE | ID: mdl-38356400

RESUMEN

Thioredoxin, glutaredoxin and peroxiredoxin systems play central roles in redox regulation, signaling and metabolism in cells. In these systems, reducing equivalents from NAD(P)H are transferred by coupled thiol-disulfide exchange reactions to redoxins which then reduce a wide array of targets. However, the characterization of redoxin activity has been unclear, with redoxins regarded as enzymes in some studies and redox metabolites in others. Consequently, redoxin activities have been quantified by enzyme kinetic parameters in vitro, and redox potentials or redox ratios within cells. By analyzing all the reactions within these systems, computational models showed that many kinetic properties attributed to redoxins were due to system-level effects. Models of cellular redoxin networks have also been used to estimate intracellular hydrogen peroxide levels, analyze redox signaling and couple omic and kinetic data to understand the regulation of these networks in disease. Computational modeling has emerged as a powerful complementary tool to traditional redoxin enzyme kinetic and cellular assays that integrates data from a number of sources into a single quantitative framework to accelerate the analysis of redoxin systems.


Asunto(s)
Glutarredoxinas , Oxidación-Reducción , Peroxirredoxinas , Tiorredoxinas , Tiorredoxinas/metabolismo , Humanos , Glutarredoxinas/metabolismo , Peroxirredoxinas/metabolismo , Peroxirredoxinas/química , Simulación por Computador , Cinética , Modelos Biológicos , Animales , Catálisis , Transducción de Señal
2.
Free Radic Biol Med ; 218: 16-25, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38574974

RESUMEN

A critical feature of the cellular antioxidant response is the induction of gene expression by redox-sensitive transcription factors. In many cells, activating these transcription factors is a dynamic process involving multiple redox steps, but it is unclear how these dynamics should be measured. Here, we show how the dynamic profile of the Schizosaccharomyces pombe Pap1 transcription factor is quantifiable by three parameters: signal amplitude, signal time and signal duration. In response to increasing hydrogen peroxide concentrations, the Pap1 amplitude decreased while the signal time and duration showed saturable increases. In co-response plots, these parameters showed a complex, non-linear relationship to the mRNA levels of four Pap1-regulated genes. We also demonstrate that hydrogen peroxide and tert-butyl hydroperoxide trigger quantifiably distinct Pap1 activation profiles and transcriptional responses. Based on these findings, we propose that different oxidants and oxidant concentrations modulate the Pap1 dynamic profile, leading to specific transcriptional responses. We further show how the effect of combination and pre-exposure stresses on Pap1 activation dynamics can be quantified using this approach. This method is therefore a valuable addition to the redox signalling toolbox that may illuminate the role of dynamics in determining appropriate responses to oxidative stress.


Asunto(s)
Peróxido de Hidrógeno , Oxidación-Reducción , Proteínas de Schizosaccharomyces pombe , Schizosaccharomyces , Transducción de Señal , Proteínas de Schizosaccharomyces pombe/metabolismo , Proteínas de Schizosaccharomyces pombe/genética , Schizosaccharomyces/metabolismo , Schizosaccharomyces/genética , Peróxido de Hidrógeno/metabolismo , terc-Butilhidroperóxido/farmacología , Proteínas Asociadas a Pancreatitis/metabolismo , Proteínas Asociadas a Pancreatitis/genética , Regulación Fúngica de la Expresión Génica , Estrés Oxidativo , Factores de Transcripción/metabolismo , Factores de Transcripción/genética , Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/metabolismo , Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/genética , Oxidantes/farmacología , Oxidantes/metabolismo
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