Evolution of Negative Cooperativity in Glutathione Transferase Enabled Preservation of Enzyme Function

Bocedi, Alessio; Fabrini, Raffaele; Bello, Mario Lo; Caccuri, Anna Maria; Federici, Giorgio; Mannervik, Bengt; Cornish‐Bowden, Athel; Ricci, Giorgio

doi:10.1074/jbc.m116.749507

Cited by 27 publications

(19 citation statements)

References 57 publications

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“…The formation of DNIC-protein complexes was previously described for bovine serum albumin [9] and for proteins of the glutathione transferase (GST) family [60,61]. The latter were extensively investigated by Ricci and co-workers, who showed that these enzymes, in particular the Tyr GSTs, have an extremely high affinity for DNIC, forming DNIC-GST complexes, whose dissociation constant attain the range of 10 −9 to 10 −12 M [62].…”

Section: Discussionmentioning

confidence: 99%

The Peroxidatic Thiol of Peroxiredoxin 1 is Nitrosated by Nitrosoglutathione but Coordinates to the Dinitrosyl Iron Complex of Glutathione

et al. 2020

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Protein S-nitrosation is an important consequence of NO●·metabolism with implications in physiology and pathology. The mechanisms responsible for S-nitrosation in vivo remain debatable and kinetic data on protein S-nitrosation by different agents are limited. 2-Cys peroxiredoxins, in particular Prx1 and Prx2, were detected as being S-nitrosated in multiple mammalian cells under a variety of conditions. Here, we investigated the kinetics of Prx1 S-nitrosation by nitrosoglutathione (GSNO), a recognized biological nitrosating agent, and by the dinitrosyl-iron complex of glutathione (DNIC-GS; [Fe(NO)2(GS)2]−), a hypothetical nitrosating agent. Kinetics studies following the intrinsic fluorescence of Prx1 and its mutants (C83SC173S and C52S) were complemented by product analysis; all experiments were performed at pH 7.4 and 25 ℃. The results show GSNO-mediated nitrosation of Prx1 peroxidatic residue ( k + N O C y s 52 = 15.4 ± 0.4 M−1. s−1) and of Prx1 Cys83 residue ( k + N O C y s 83 = 1.7 ± 0.4 M−1. s−1). The reaction of nitrosated Prx1 with GSH was also monitored and provided a second-order rate constant for Prx1Cys52NO denitrosation of k − N O C y s 52 = 14.4 ± 0.3 M−1. s−1. In contrast, the reaction of DNIC-GS with Prx1 did not nitrosate the enzyme but formed DNIC-Prx1 complexes. The peroxidatic Prx1 Cys was identified as the residue that more rapidly replaces the GS ligand from DNIC-GS ( k D N I C C y s 52 = 7.0 ± 0.4 M−1. s−1) to produce DNIC-Prx1 ([Fe(NO)2(GS)(Cys52-Prx1)]−). Altogether, the data showed that in addition to S-nitrosation, the Prx1 peroxidatic residue can replace the GS ligand from DNIC-GS, forming stable DNIC-Prx1, and both modifications disrupt important redox switches.

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Section: Discussionmentioning

confidence: 99%

The Peroxidatic Thiol of Peroxiredoxin 1 is Nitrosated by Nitrosoglutathione but Coordinates to the Dinitrosyl Iron Complex of Glutathione

et al. 2020

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“…Cooperativity in BCR-ABL, a tyrosine kinase identified as a hallmark for myeloid leukaemia can be either negative [54, 55] or positive [26] depending on the coupling between the nucleotide and substrate binding sites. In CaMKII, as reported here, the nucleotide and substrate binding modules are again recruited for the formation of positive trans-subunit couplings.…”

Section: Discussionmentioning

confidence: 99%

Conformational coupling by trans-phosphorylation in calcium calmodulin dependent kinase II

2019

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The calcium calmodulin-dependent protein kinase II (CaMKII) is a dodecameric holoenzyme important for encoding memory. Its activation, triggered by binding of calcium-calmodulin, persists autonomously after calmodulin dissociation. One (receiver) kinase captures and subsequently phosphorylates the regulatory domain peptide of a donor kinase forming a chained dimer as the first stage of autonomous activation. Protein dynamics simulations examined the conformational changes triggered by dimer formation and phosphorylation, aimed to provide a molecular rationale for human mutations that result in learning disabilities. Ensembles generated from X-ray crystal structures were characterized by network centrality and community analysis. Mutual information related collective motions to local fragment dynamics encoded with a structural alphabet. Implicit solvent tCONCOORD conformational ensembles revealed the dynamic architecture of inactive kinase domains was co-opted in the activated dimer but the network hub shifted from the nucleotide binding cleft to the captured peptide. Explicit solvent molecular dynamics (MD) showed nucleotide and substrate binding determinants formed coupled nodes in long-range signal relays between regulatory peptides in the dimer. Strain in the extended captured peptide was balanced by reduced flexibility of the receiver kinase C-lobe core. The relays were organized around a hydrophobic patch between the captured peptide and a key binding helix. The human mutations aligned along the relays. Thus, these mutations could disrupt the allosteric network alternatively, or in addition, to altered binding affinities. Non-binding protein sectors distant from the binding sites mediated the allosteric signalling; providing possible targets for inhibitor design. Phosphorylation of the peptide modulated the dielectric of its binding pocket to strengthen the patch, non-binding sectors, domain interface and temporal correlations between parallel relays. These results provide the molecular details underlying the reported positive kinase cooperativity to enrich the discussion on how autonomous activation by phosphorylation leads to long-term behavioural effects.

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“…This mechanism preserves GSTP1-1 from complete inactivation when it is involved in the DNDGIC detoxification, maintaining its classical conjugating activity even when an excess of NO is produced in the cell. This particular self-preservation has been also found also in other GST isoenzymes like the Alpha and Mu GSTs but not in bacterial GSTs, suggesting that this property has been acquired only in the more recently evolved organisms [25].…”

Section: Introductionmentioning

confidence: 95%

Glutathione Transferase P1-1 an Enzyme Useful in Biomedicine and as Biomarker in Clinical Practice and in Environmental Pollution

et al. 2019

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Glutathione transferase P1-1 (GSTP1-1) is expressed in some human tissues and is abundant in mammalian erythrocytes (here termed e-GST). This enzyme is able to detoxify the cell from endogenous and exogenous toxic compounds by using glutathione (GSH) or by acting as a ligandin. This review collects studies that propose GSTP1-1 as a useful biomarker in different fields of application. The most relevant studies are focused on GSTP1-1 as a biosensor to detect blood toxicity in patients affected by kidney diseases. In fact, this detoxifying enzyme is over-expressed in erythrocytes when unusual amounts of toxins are present in the body. Here we review articles concerning the level of GST in chronic kidney disease patients, in maintenance hemodialysis patients and to assess dialysis adequacy. GST is also over-expressed in autoimmune disease like scleroderma, and in kidney transplant patients and it may be used to check the efficiency of transplanted kidneys. The involvement of GSTP in the oxidative stress and in other human pathologies like cancer, liver and neurodegenerative diseases, and psychiatric disorders is also reported. Promising applications of e-GST discussed in the present review are its use for monitoring human subjects living in polluted areas and mammals for veterinary purpose.

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Evolution of Negative Cooperativity in Glutathione Transferase Enabled Preservation of Enzyme Function

Cited by 27 publications

References 57 publications

The Peroxidatic Thiol of Peroxiredoxin 1 is Nitrosated by Nitrosoglutathione but Coordinates to the Dinitrosyl Iron Complex of Glutathione

The Peroxidatic Thiol of Peroxiredoxin 1 is Nitrosated by Nitrosoglutathione but Coordinates to the Dinitrosyl Iron Complex of Glutathione

Conformational coupling by trans-phosphorylation in calcium calmodulin dependent kinase II

Glutathione Transferase P1-1 an Enzyme Useful in Biomedicine and as Biomarker in Clinical Practice and in Environmental Pollution

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