Stability of the domain interface contributes towards the catalytic function at the H-site of class alpha glutathione transferase A1-1

Balchin, David; Fanucchi, Sylvia; Achilonu, Ikechukwu; Adamson, R.J.; Burke, Jonathan; Fernandes, Manuel A.; Gildenhuys, Samantha; Dirr, Heini W.

doi:10.1016/j.bbapap.2010.09.003

Cited by 15 publications

(17 citation statements)

References 48 publications

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“…The C-terminal helix region of GSTA1-1 is likewise known to behave in an independent manner compared with the remainder of the protein, and it is likely that the low temperature transition in the DSC thermogram of GSTA1-1 corresponds to changes in this element. However, previous studies have shown that the C terminus retains helical structure in this temperature regime (42,44). These results, in addition to the reversibility of the DSC scan up to 50°C, suggest that the lower temperature transitions are not due to unfolding per se, but may be due to temperaturedependent sampling of different locations by the C-terminal helix, or restructuring of its tertiary contacts.…”

Section: Resultsmentioning

confidence: 48%

Ensemble Perspective for Catalytic Promiscuity

Honaker

Acchione

Sumida

et al. 2011

Journal of Biological Chemistry

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Background: Catalytic promiscuity is common, but its molecular basis is poorly understood. Results: Differential scanning calorimetry reveals the local active site conformational landscape of a promiscuous detoxification enzyme, glutathione transferase A1-1, as "smooth" and heterogeneous. Conclusion: Facile conformational exchange facilitates substrate promiscuity. Significance: The results provide the first thermodynamic basis for catalytic promiscuity.

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Section: Resultsmentioning

confidence: 48%

Ensemble Perspective for Catalytic Promiscuity

Honaker

Acchione

Sumida

et al. 2011

Journal of Biological Chemistry

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“…GSTA1-1 is a promiscuous enzyme, whereas GSTA4-4 has much higher substrate specificity and catalytic efficiency toward alkenal substrates, such as HNE, although it also maintains negligible stereoselectivity toward the individual enantiomers. The role of numerous interactions involving regions, such as the C-terminus or the domain-domain interface, have been explored with respect to enzyme stability and dynamics as well as the relationship to catalytic function (Adman et al, 2001; Balchin et al, 2010; Dirr et al, 2005; Dirr and Wallace, 1999; Gustafsson et al, 1999; Ibarra et al, 2001; Kuhnert et al, 2005; Mosebi et al, 2003; Nieslanik and Atkins, 2000; Nieslanik et al, 1999, 2001; Nilsson et al, 2002). Both isoforms utilize three substrate recognition regions (the β1-α1 region, the end of the α4-helix, and the C-terminus) to construct the H-sites in the folded protein.…”

Section: Structural Characterizationsmentioning

confidence: 99%

Interactions of glutathione transferases with 4-hydroxynonenal

Balogh

Atkins

2011

Drug Metabolism Reviews

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Electrophilic products of lipid peroxidation are important contributors to the progression of several pathological states. The prototypical α,β–unsaturated aldehyde, 4-hydroxynonenal (HNE), triggers cellular events associated with oxidative stress, which can be curtailed by the glutathione-dependent elimination of HNE. The glutathione transferases (GSTs) are a major determinate of the intracellular concentration of HNE and can influence susceptibility to toxic effects, particularly when HNE and GST levels are altered in disease states. In this article, we provide a brief summary of the cellular effects of HNE, followed by a review of its GST-catalyzed detoxification, with an emphasis on the structural attributes that play an important role in the interactions with alpha-class GSTs. Some of the key determining characteristics that impart high alkenal activity reside in the unique C-terminal interactions of the GSTA4-4 enzyme. Studies encompassing both kinetic and structural analyses of related isoforms will be highlighted, with additional attention to stereochemical aspects that demonstrate the capacity of GSTA4-4 to detoxify both enantiomers of the biologically relevant racemic mixture while generating a select set of diastereomeric products with subsequent implications. A summary of the literature that examines the interplay between GSTs and HNE in model systems relevant to oxidative stress will also be discussed to demonstrate the magnitude of importance of GSTs in the overall detoxification scheme.

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“…It has been recently proposed that the level of functional promiscuity of the GST enzymes is mediated by conformational flexibility and stability of the protein structure outside the active center (Balchin et al, 2010). This comes in agreement with the fact that GST subunits undergo significant conformational changes at substrate binding suggesting the induced fit mechanism (Neuefeind, Huber, Dasenbrock, Prade, & Bieseler, 1997;Sheehan et al, 2001).…”

Section: Usage Examplementioning

confidence: 77%

“…The SSPs Leu19, Tyr22, and Thr23 in α1 of the domain 1 and Phe157 in α6 of the domain 2 form interdomain contacts within one subunit by interacting with a hydrophobic pocket between α1 and α3 of the domain 1, and α6-8 of the domain 2. These specific contacts at the domain-domain interface can mediate the catalytic function by providing shape and flexibility to the active site for complementary interactions with the substrate (Balchin et al, 2010).…”

Section: Usage Examplementioning

confidence: 99%

Zebra: a web server for bioinformatic analysis of diverse protein families

Suplatov

Kirilin

Takhaveev

et al. 2013

Journal of Biomolecular Structure and Dynamics

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During evolution of proteins from a common ancestor, one functional property can be preserved while others can vary leading to functional diversity. A systematic study of the corresponding adaptive mutations provides a key to one of the most challenging problems of modern structural biology - understanding the impact of amino acid substitutions on protein function. The subfamily-specific positions (SSPs) are conserved within functional subfamilies but are different between them and, therefore, seem to be responsible for functional diversity in protein superfamilies. Consequently, a corresponding method to perform the bioinformatic analysis of sequence and structural data has to be implemented in the common laboratory practice to study the structure-function relationship in proteins and develop novel protein engineering strategies. This paper describes Zebra web server - a powerful remote platform that implements a novel bioinformatic analysis algorithm to study diverse protein families. It is the first application that provides specificity determinants at different levels of functional classification, therefore addressing complex functional diversity of large superfamilies. Statistical analysis is implemented to automatically select a set of highly significant SSPs to be used as hotspots for directed evolution or rational design experiments and analyzed studying the structure-function relationship. Zebra results are provided in two ways - (1) as a single all-in-one parsable text file and (2) as PyMol sessions with structural representation of SSPs. Zebra web server is available at http://biokinet.belozersky.msu.ru/zebra .

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Stability of the domain interface contributes towards the catalytic function at the H-site of class alpha glutathione transferase A1-1

Cited by 15 publications

References 48 publications

Ensemble Perspective for Catalytic Promiscuity

Ensemble Perspective for Catalytic Promiscuity

Interactions of glutathione transferases with 4-hydroxynonenal

Zebra: a web server for bioinformatic analysis of diverse protein families

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