Glyoxalase Enzymes in Trypanosomatids

Silva, Marta Sousa; Ferreira, António E. N.; Gomes, Ricardo A.; Tomás, Ana M.; Freire, Ana Ponces; Cordeiro, Carlos

doi:10.1002/9783527670383.ch8

Cited by 3 publications

(1 citation statement)

References 44 publications

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“…Intriguingly, we observed a significant increase in the concentration of D-LDH in NO-resistant parasites after exposure to NO, and such increase was accompanied by increased LDH enzymatic activity. In L. major, D-lactate produced via methylglyoxal metabolism would be converted to pyruvate by a D-LDH, with the resulting molecule feeding the tricarboxylic acid cycle (TCA) and other pathways [ 72 , 73 , 74 ]. As the methylglyoxal is a toxic glycolytic metabolite, we hypothesize that the increase in glucose uptake and, consequently, in the production of methylglyoxal may occur in response to nitrosative stress in NO-resistant parasites challenged with NO, leading to upregulation of D-LDH abundance and activity in these parasites.…”

Section: Discussionmentioning

confidence: 99%

Nitric Oxide Resistance in Leishmania (Viannia) braziliensis Involves Regulation of Glucose Consumption, Glutathione Metabolism and Abundance of Pentose Phosphate Pathway Enzymes

et al. 2022

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In American Tegumentary Leishmaniasis production of cytokines, reactive oxygen species and nitric oxide (NO) by host macrophages normally lead to parasite death. However, some Leishmania braziliensis strains exhibit natural NO resistance. NO-resistant strains cause more lesions and are frequently more resistant to antimonial treatment than NO-susceptible ones, suggesting that NO-resistant parasites are endowed with specific mechanisms of survival and persistence. To tests this, we analyzed the effect of pro- and antioxidant molecules on the infectivity in vitro of L. braziliensis strains exhibiting polar phenotypes of resistance or susceptibility to NO. In addition, we conducted a comprehensive quantitative mass spectrometry-based proteomics analysis of those parasites. NO-resistant parasites were more infective to peritoneal macrophages, even in the presence of high levels of reactive species. Principal component analysis of protein concentration values clearly differentiated NO-resistant from NO-susceptible parasites, suggesting that there are natural intrinsic differences at molecular level among those strains. Upon NO exposure, NO-resistant parasites rapidly modulated their proteome, increasing their total protein content and glutathione (GSH) metabolism. Furthermore, NO-resistant parasites showed increased glucose analogue uptake, and increased abundance of phosphotransferase and G6PDH after nitrosative challenge, which can contribute to NADPH pool maintenance and fuel the reducing conditions for the recovery of GSH upon NO exposure. Thus, increased glucose consumption and GSH-mediated redox capability may explain the natural resistance of L. braziliensis against NO.

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Section: Discussionmentioning

confidence: 99%

Nitric Oxide Resistance in Leishmania (Viannia) braziliensis Involves Regulation of Glucose Consumption, Glutathione Metabolism and Abundance of Pentose Phosphate Pathway Enzymes

et al. 2022

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The glyoxalase pathway in protozoan parasites

Silva

Ferreira

Gomes

et al. 2012

International Journal of Medical Microbiology

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The glyoxalase pathway: the first hundred years… and beyond

Silva

Gomes

Ferreira

et al. 2013

Biochemical Journal

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222

207

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The discovery of the enzymatic formation of lactic acid from methylglyoxal dates back to 1913 and was believed to be associated with one enzyme termed ketonaldehydemutase or glyoxalase, the latter designation prevailed. However, in 1951 it was shown that two enzymes were needed and that glutathione was the required catalytic co-factor. The concept of a metabolic pathway defined by two enzymes emerged at this time. Its association to detoxification and anti-glycation defence are its presently accepted roles, since methylglyoxal exerts irreversible effects on protein structure and function, associated with misfolding. This functional defence role has been the rationale behind the possible use of the glyoxalase pathway as a therapeutic target, since its inhibition might lead to an increased methylglyoxal concentration and cellular damage. However, metabolic pathway analysis showed that glyoxalase effects on methylglyoxal concentration are likely to be negligible and several organisms, from mammals to yeast and protozoan parasites, show no phenotype in the absence of one or both glyoxalase enzymes. The aim of the present review is to show the evolution of thought regarding the glyoxalase pathway since its discovery 100 years ago, the current knowledge on the glyoxalase enzymes and their recognized role in the control of glycation processes.

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Glyoxalase Enzymes in Trypanosomatids

Cited by 3 publications

References 44 publications

Nitric Oxide Resistance in Leishmania (Viannia) braziliensis Involves Regulation of Glucose Consumption, Glutathione Metabolism and Abundance of Pentose Phosphate Pathway Enzymes

Nitric Oxide Resistance in Leishmania (Viannia) braziliensis Involves Regulation of Glucose Consumption, Glutathione Metabolism and Abundance of Pentose Phosphate Pathway Enzymes

The glyoxalase pathway in protozoan parasites

The glyoxalase pathway: the first hundred years… and beyond

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