Reprogramming of Trypanosoma cruzi metabolism triggered by parasite interaction with the host cell extracellular matrix
Eliciane Cevolani MattosGisele André Baptista CanutoNubia Carolina MancholaRubens Daniel Miserani MagalhãesThomas W.M. CrozierDouglas J. LamontMarina Franco Maggi TavaresWalter ColliMichael A. J. FergusonMaria Júlia Manso Alves
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Abstract:
Trypanosoma cruzi, the etiological agent of Chagas' disease, affects 8 million people predominantly living in socioeconomic underdeveloped areas. T. cruzi trypomastigotes (Ty), the classical infective stage, interact with the extracellular matrix (ECM), an obligatory step before invasion of almost all mammalian cells in different tissues. Here we have characterized the proteome and phosphoproteome of T. cruzi trypomastigotes upon interaction with ECM (MTy) and the data are available via ProteomeXchange with identifier PXD010970. Proteins involved with metabolic processes (such as the glycolytic pathway), kinases, flagellum and microtubule related proteins, transport-associated proteins and RNA/DNA binding elements are highly represented in the pool of proteins modified by phosphorylation. Further, important metabolic switches triggered by this interaction with ECM were indicated by decreases in the phosphorylation of hexokinase, phosphofructokinase, fructose-2,6-bisphosphatase, phosphoglucomutase, phosphoglycerate kinase in MTy. Concomitantly, a decrease in the pyruvate and lactate and an increase of glucose and succinate contents were detected by GC-MS. These observations led us to focus on the changes in the glycolytic pathway upon binding of the parasite to the ECM. Inhibition of hexokinase, pyruvate kinase and lactate dehydrogenase activities in MTy were observed and this correlated with the phosphorylation levels of the respective enzymes. Putative kinases involved in protein phosphorylation altered upon parasite incubation with ECM were suggested by in silico analysis. Taken together, our results show that in addition to cytoskeletal changes and protease activation, a reprogramming of the trypomastigote metabolism is triggered by the interaction of the parasite with the ECM prior to cell invasion and differentiation into amastigotes, the multiplicative intracellular stage of T. cruzi in the vertebrate host.Keywords:
Hexokinase
Phosphoglycerate kinase
The activity of glycolytic enzymes (lactate dehydrogenase, pyruvate kinase, hexokinase), content of metabolites (lactate, pyruvate, ATP, 2,3-DPG) and haemolytic stability of rat erythrocytes at the action of chronic X-irradiation at a daily dose 0.258 mC/kg, 2.58 mC/kg, 5.16 mC/kg during 90, 60 and 30 days, accordingly, have been investigated. It was shown, that the glycolytic enzymes activity of female rats in different seasons may vary in wide limits. A general tendency to the decrease of lactate dehydrogenase activity is revealed, but the beginning effects under the irradiation at a daily dose of 2.58 mC/kg and 5.16 mC/kg may be differently directed. The analogous tendencies are found in the change of hexokinase activity. The changes in pyruvate kinase activity correlated with erythrocytes haemolytic stability. The data obtained prove that changes in the direction of glycolytic enzymes activity under the irradiation depend on the initial level, which is caused by seasonal peculiarities of physiological state.
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Specific activity
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Hexokinase
Phosphofructokinase 1
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The full time courses of some important metabolites of the glycolysis of human erythrocytes are reported following pH-shifts from pH 7.4 to 8.1 and from 8.1 to 6.9. The regulatory enzymes which are affected by the pH-transitions have been identified by computer simulation using a mathematical model of the erythrocyte glycolysis. It is concluded that in the transition to pH 8.1 the hexokinase-phosphofructokinase system is activated and the pyruvate kinase is inhibited. At pH 6.9 the hexokinase-phosphofructokinase system and the bisphosphoglycerate mutase are inhibited whereas the non-glycolytic ATP-consuming processes seem to be activated.
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Phosphoglycerate mutase
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Mutase
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The most significant metabolic features of malignant tumors is their highly effective glycolysis, i.e., the . The active degree in tumor glycolysis is closely related to cancer growth and aggressive. Although the mechanism of efficient glycolysis in tumor are involved in oncogene events, the abnormalities of key enzymes in glycolysis, play a pivotal role in tumor Warburg effect. Among others, there is more significant alterations of hexokinase (HK ) in the expression, subcellular distribution and kinetics, and which is is bound up with the prominent metabolic phenotype, proliferation and apoptosis of malignant cell. HK-Ⅱ may be a potential target for exploring the diagnosis and therapy of tumor.
Key words:
Hexokinase; Tumor; Glycolysis; Warburg effect
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Warburg Effect
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Anaerobic glycolysis
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Glucose 6-phosphate
Carbohydrate Metabolism
Metabolic pathway
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The objective of this work was to investigate the influence of phosphoglycerate kinase-1 (PGK1) and pyruvate kinase-M2 (PKM2) activity on glycolysis, myofibrillar proteins, calpain system, and apoptosis pathways of postmortem muscle. The activity of PGK1 and PKM2 was regulated by their inhibitors and activators to construct the postmortem glycolysis vitro model and then incubated at 4 °C for 24 h. The results showed that compared to PGK1 and PKM2 inhibitors groups, the addition of PGK1 and PKM2 activators could accelerate glycogen consumption, ATP and lactate production, while declining pH value. Moreover, the addition of PGK1 and PKM2 activators could increase desmin degradation, μ-calpain activity, and caspase-3 abundance. Interestingly, troponin-T degradation was significantly increased both in PKM2 inhibitor and activator groups. It was suggested that PGK1 and PKM2 might be used as robust indicators to regulate meat quality by affecting the glycolysis, myofibrillar proteins, μ-calpain and apoptosis pathways in postmortem muscle.
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Phosphoglycerate kinase
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Normal and precancerous livers as well as primary and transplanted hepatomas are studied for glycogen content, hexokinase- and glucokinase activity, at the same time measuring glycolysis in the high-speed supernatants of these tissues with different substrates and additives. Experimental results show that: 1) normal and precancerous rat livers have low hexokinase activity and low glycolysis, but high glucokinase activity and high glycogen content; 2) primary DAB hepatomas. on the contrary, have high hexokinase activity and raised glycolysis as well as low glycokinase activity and low glycogen content; 3) transplantable DAB- as well as DENA-hepatomas have high hexokinase activity and high glycolyses. while neither glucokinase activity nor glycogen content have been found; 4) when using glucose as substrate and adding exogenous hexokinase. there is a considerable increase in formation of lactic acid in all tissue supernatants investigated; 5) if glucose-6-phosphate is used instead of glucose, a considerable increase of glycolysis is noted as well. It is concluded from the results obtained that the hexokinase reaction limits the extent of glycolysis in these tissues.
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