Structural basis for the modulation of plant cytosolic triosephosphate isomerase activity by mimicry of redox‐based modifications

Castro‐Torres, Eduardo; Jiménez‐Sandoval, Pedro; Romero‐Romero, Sergio; Fuentes-Pascacio, Alma; Lopez‐Castillo, Laura Margarita; Díaz‐Quezada, Corina; Fernández‐Velasco, D. Alejandro; Torres‐Larios, Alfredo; Brieba, Luis G.

doi:10.1111/tpj.14375

Cited by 9 publications

(7 citation statements)

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“…In a given protein, all Cys residues are not equally susceptible to this modification, as a result of the value of their p K a . A basic environment or the proximity of a metal cation are key determinants for the tendency of thiol groups to become deprotonated and consequently be affected by oxidation and spontaneous S -glutathionylation [ 222 , 223 , 224 , 225 , 226 , 227 ]. In animal systems, protein S -glutathionylation is also mediated enzymatically by glutathione S -transferase Pi [ 228 , 229 , 230 ].…”

Section: Protein S -Glutathionylation: Roles Of Glutathione In the Protection And Regulation Of Protein Functions Undementioning

confidence: 99%

“…If the residue is located in the vicinity of the active site, its ligation to glutathione can restrict the access of the substrate to the site by causing steric hindrance [ 227 ]. Following S -glutathionylation, enzymes can also undergo conformational modifications, often leading to an inhibition of enzymatic activity [ 225 , 226 , 227 ]. In other cases, protein S -glutathionylation directly interferes with oligomerization or signal transduction [ 226 , 232 ].…”

Section: Protein S -Glutathionylation: Roles Of Glutathione In the Protection And Regulation Of Protein Functions Undementioning

confidence: 99%

“…Following S -glutathionylation, enzymes can also undergo conformational modifications, often leading to an inhibition of enzymatic activity [ 225 , 226 , 227 ]. In other cases, protein S -glutathionylation directly interferes with oligomerization or signal transduction [ 226 , 232 ].…”

Section: Protein S -Glutathionylation: Roles Of Glutathione In the Protection And Regulation Of Protein Functions Undementioning

confidence: 99%

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Glutathione Metabolism in Plants under Stress: Beyond Reactive Oxygen Species Detoxification

2021

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Glutathione is an essential metabolite for plant life best known for its role in the control of reactive oxygen species (ROS). Glutathione is also involved in the detoxification of methylglyoxal (MG) which, much like ROS, is produced at low levels by aerobic metabolism under normal conditions. While several physiological processes depend on ROS and MG, a variety of stresses can dramatically increase their concentration leading to potentially deleterious effects. In this review, we examine the structure and the stress regulation of the pathways involved in glutathione synthesis and degradation. We provide a synthesis of the current knowledge on the glutathione-dependent glyoxalase pathway responsible for MG detoxification. We present recent developments on the organization of the glyoxalase pathway in which alternative splicing generate a number of isoforms targeted to various subcellular compartments. Stress regulation of enzymes involved in MG detoxification occurs at multiple levels. A growing number of studies show that oxidative stress promotes the covalent modification of proteins by glutathione. This post-translational modification is called S-glutathionylation. It affects the function of several target proteins and is relevant to stress adaptation. We address this regulatory function in an analysis of the enzymes and pathways targeted by S-glutathionylation.

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Section: Protein S -Glutathionylation: Roles Of Glutathione In the Protection And Regulation Of Protein Functions Undementioning

confidence: 99%

Section: Protein S -Glutathionylation: Roles Of Glutathione In the Protection And Regulation Of Protein Functions Undementioning

confidence: 99%

Section: Protein S -Glutathionylation: Roles Of Glutathione In the Protection And Regulation Of Protein Functions Undementioning

confidence: 99%

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Glutathione Metabolism in Plants under Stress: Beyond Reactive Oxygen Species Detoxification

2021

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“…Residues SmTPI-C221 and GlTPI-C222 localize near the YGGS motif that is necessary to assemble the closed TPI conformation via hydrogen and hydrophobic interactions with loop 6. Point mutations in GlTPI-C222 and the equivalent cysteine residue in the cytosolic TPI from Arabidopsis reduced the enzymatic activity of those enzymes [69,70]. Point mutations in SmTPI-C221 partially abrogate catalysis, having a reduction of approximately 10-fold in catalytic efficiency.…”

Section: Discussionmentioning

confidence: 99%

Crystal structures of Triosephosphate Isomerases from Taenia solium and Schistosoma mansoni provide insights for vaccine rationale and drug design against helminth parasites

et al. 2020

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Triosephosphate isomerases (TPIs) from Taenia solium (TsTPI) and Schistosoma mansoni (SmTPI) are potential vaccine and drug targets against cysticercosis and schistosomiasis, respectively. This is due to the dependence of parasitic helminths on glycolysis and because those proteins elicit an immune response, presumably due to their surface localization. Here we report the crystal structures of TsTPI and SmTPI in complex with 2-phosphoglyceric acid (2-PGA). Both TPIs fold into a dimeric (β-α) 8 barrel in which the dimer interface consists of α-helices 2, 3, and 4, and swapping of loop 3. TPIs from parasitic helminths harbor a region of three amino acids knows as the SXD/E insert (S155 to E157 and S157 to D159 in TsTPI and SmTPI, respectively). This insert is located between α5 and β6 and is proposed to be the main TPI epitope. This region is part of a solvent-exposed 3 10 -helix that folds into a hook-like structure. The crystal structures of TsTPI and SmTPI predicted conformational epitopes that could be used for vaccine design. Surprisingly, the epitopes corresponding to the SXD/E inserts are not the ones with the greatest immunological potential. SmTPI, but not TsTPI, habors a sole solvent exposed cysteine (SmTPI-S230) and alterations in this residue decrease catalysis. The latter suggests that thiol-conjugating agents could be used to target SmTPI. In sum, the crystal structures of SmTPI and TsTPI are a blueprint for targeted schistosomiasis and cysticercosis drug and vaccine development. Author summaryBecause of the worldwide prevalence of schistosomiasis and cysticercosis, it is critical to develop drugs and vaccines against their causative agents. The glycolytic enzyme triosephosphate isomerase (TPI) is a dual-edged sword against diseases caused by parasitic helminths. This is because helminths heavily depend on glycolysis for energy and because the PLOS Neglected Tropical Diseases | https://doi.

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“…Interestingly, increases in glycolysis play an important role in combating oxidative stress. The activation of the pentose-phosphate pathway (PPP), an offshoot of glycolysis, alleviates oxidative stress by promoting glutathione (GSH) redox homeostasis (18,19). Oxidative stress leads to increases in PSSG (protein S-glutathionylation), the covalent linkage of GSH to the thiol group of protein cysteines.…”

mentioning

confidence: 99%

Dysregulation of Pyruvate Kinase M2 Promotes Inflammation in a Mouse Model of Obese Allergic Asthma

Manuel

Wetering

MacPherson

et al. 2021

Am J Respir Cell Mol Biol

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Obesity is a risk factor for the development of asthma and represents a difficult-to-treat disease phenotype. Aerobic glycolysis is emerging as a key feature of asthma, and changes in glucose metabolism are linked to leukocyte activation and adaptation to oxidative stress. Dysregulation of PKM2 (pyruvate kinase M2), the enzyme that catalyzes the last step of glycolysis, contributes to house dust mite (HDM)-induced airway inflammation and remodeling in lean mice. It remains unclear whether glycolytic reprogramming and dysregulation of PKM2 also contribute to obese asthma. The goal of the present study was to elucidate the functional role of PKM2 in a murine model of obese allergic asthma. We evaluated the small molecule activator of PKM2, TEPP46, and assessed the role of PKM2 using conditional ablation of the Pkm2 allele from airway epithelial cells. In obese C57BL/6NJ mice, parameters indicative of glycolytic reprogramming remained unchanged in the absence of stimulation with HDM. Obese mice that were subjected to HDM showed evidence of glycolytic reprogramming, and treatment with TEPP46 diminished airway inflammation, whereas parameters of airway remodeling were unaffected. Epithelial ablation of Pkm2 decreased central airway resistance in both lean and obese allergic mice in addition to decreasing inflammatory cytokines in the lung tissue. Lastly, we highlight a novel role for PKM2 in the regulation of glutathione-dependent protein oxidation in the lung tissue of obese allergic mice via a putative IFN-g-glutaredoxin1 pathway. Overall, targeting metabolism and protein oxidation may be a novel treatment strategy for obese allergic asthma.

show abstract

Structural basis for the modulation of plant cytosolic triosephosphate isomerase activity by mimicry of redox‐based modifications

Cited by 9 publications

References 70 publications

Glutathione Metabolism in Plants under Stress: Beyond Reactive Oxygen Species Detoxification

Glutathione Metabolism in Plants under Stress: Beyond Reactive Oxygen Species Detoxification

Crystal structures of Triosephosphate Isomerases from Taenia solium and Schistosoma mansoni provide insights for vaccine rationale and drug design against helminth parasites

Dysregulation of Pyruvate Kinase M2 Promotes Inflammation in a Mouse Model of Obese Allergic Asthma

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