Trypanosoma evansi contains two auxiliary enzymes of glycolytic metabolism: Phosphoenolpyruvate carboxykinase and pyruvate phosphate dikinase

Rivero, Luz Amira; Concepción, Juan Luís; Quintero-Troconis, Ender; Quiñones, Wilfredo; Michels, Paul A.M.; Acosta, Héctor

doi:10.1016/j.exppara.2016.03.003

Cited by 7 publications

(5 citation statements)

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“…Metabolomic analysis with labelled glucose also failed to reveal evidence for GNG [11]. Consequently, it is often stated that BSF trypanosomes depend ‘exclusively’ [14,15,16,17] or ‘entirely’ [18,19] on glycolysis, using glucose as a substrate, for ATP production (reviewed in [20,21]). For this reason, the glycolytic pathway has been considered to be a promising target for antitrypanosomal drug discovery [6].…”

Section: Introductionmentioning

confidence: 99%

Gluconeogenesis using glycerol as a substrate in bloodstream-form Trypanosoma brucei

et al. 2018

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Bloodstream form African trypanosomes are thought to rely exclusively upon glycolysis, using glucose as a substrate, for ATP production. Indeed, the pathway has long been considered a potential therapeutic target to tackle the devastating and neglected tropical diseases caused by these parasites. However, plasma membrane glucose and glycerol transporters are both expressed by trypanosomes and these parasites can infiltrate tissues that contain glycerol. Here, we show that bloodstream form trypanosomes can use glycerol for gluconeogenesis and for ATP production, particularly when deprived of glucose following hexose transporter depletion. We demonstrate that Trypanosoma brucei hexose transporters 1 and 2 (THT1 and THT2) are localized to the plasma membrane and that knockdown of THT1 expression leads to a growth defect that is more severe when THT2 is also knocked down. These data are consistent with THT1 and THT2 being the primary routes of glucose supply for the production of ATP by glycolysis. However, supplementation of the growth medium with glycerol substantially rescued the growth defect caused by THT1 and THT2 knockdown. Metabolomic analyses with heavy-isotope labelled glycerol demonstrated that trypanosomes take up glycerol and use it to synthesize intermediates of gluconeogenesis, including fructose 1,6-bisphosphate and hexose 6-phosphates, which feed the pentose phosphate pathway and variant surface glycoprotein biosynthesis. We used Cas9-mediated gene knockout to demonstrate a gluconeogenesis-specific, but fructose-1,6-bisphosphatase (Tb927.9.8720)-independent activity, converting fructose 1,6-bisphosphate into fructose 6-phosphate. In addition, we observed increased flux through the tricarboxylic acid cycle and the succinate shunt. Thus, contrary to prior thinking, gluconeogenesis can operate in bloodstream form T. brucei. This pathway, using glycerol as a physiological substrate, may be required in mammalian host tissues.

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Section: Introductionmentioning

confidence: 99%

Gluconeogenesis using glycerol as a substrate in bloodstream-form Trypanosoma brucei

et al. 2018

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“…10: 200302 Entamoeba histolytica [21] and kinetoplastids of clinical interests, such as T. brucei, T. cruzi and Leishmania spp. [4,[22][23][24][25][26][27][28].…”

Section: Phosphoglycerate Kinasementioning

confidence: 99%

“…Studies of this parasite's metabolism involved glycolysis, including its enzymes like PGK. Rivero et al [26] have shown that this parasite (strain TEVA 1), residing in the blood, has a more complex metabolism than has been postulated for bloodstream-form T. brucei. They showed that PGK activity occurs mainly within glycosomes, but it was not the only source for ATP synthesis within the organelles.…”

Section: Pgk In African Trypanosomesmentioning

confidence: 99%

“…They showed that PGK activity occurs mainly within glycosomes, but it was not the only source for ATP synthesis within the organelles. Additional production of glycosomal ATP, necessary for other processess such as biosynthetic pathways compartmentalized in the glycosomes, was attributed to phosphoenolpyruvate carboxykinase (PEPCK) and pyruvate phosphate dikase (PPDK) [26]. Although there are so far no reports about the characterization of PGK isoenzymes in T. evansi , analysis of its genome showed that it has four pgk genes (table 3).…”

Section: Diplonemid and Kinetoplastid Protistsmentioning

confidence: 99%

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Phosphoglycerate kinase: structural aspects and functions, with special emphasis on the enzyme from Kinetoplastea

et al. 2020

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Phosphoglycerate kinase (PGK) is a glycolytic enzyme that is well conserved among the three domains of life. PGK is usually a monomeric enzyme of about 45 kDa that catalyses one of the two ATP-producing reactions in the glycolytic pathway, through the conversion of 1,3-bisphosphoglycerate (1,3BPGA) to 3-phosphoglycerate (3PGA). It also participates in gluconeogenesis, catalysing the opposite reaction to produce 1,3BPGA and ADP. Like most other glycolytic enzymes, PGK has also been catalogued as a moonlighting protein, due to its involvement in different functions not associated with energy metabolism, which include pathogenesis, interaction with nucleic acids, tumorigenesis progression, cell death and viral replication. In this review, we have highlighted the overall aspects of this enzyme, such as its structure, reaction kinetics, activity regulation and possible moonlighting functions in different protistan organisms, especially both free-living and parasitic Kinetoplastea. Our analysis of the genomes of different kinetoplastids revealed the presence of open-reading frames (ORFs) for multiple PGK isoforms in several species. Some of these ORFs code for unusually large PGKs. The products appear to contain additional structural domains fused to the PGK domain. A striking aspect is that some of these PGK isoforms are predicted to be catalytically inactive enzymes or ‘dead’ enzymes. The roles of PGKs in kinetoplastid parasites are analysed, and the apparent significance of the PGK gene duplication that gave rise to the different isoforms and their expression in Trypanosoma cruzi is discussed.

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“…The enzymes catalyzing the last three glycolytic reactions (phosphoglycerate mutase, enolase, and pyruvate kinase) have a cytosolic location and are not part of the glycosomal machinery. This is the case for both T. b. brucei and T. evansi , two evolutionary related Trypanozoon parasites [ 48 ] displaying an identical subcellular localization of their glycolytic enzymes [ 49 , 50 ]. ENO is a glycolytic enzyme that catalyzes the reversible conversion of D -2-phosphoglycerate to phosphoenolpyruvate.…”

Section: Introductionmentioning

confidence: 99%

The History of Anti-Trypanosome Vaccine Development Shows That Highly Immunogenic and Exposed Pathogen-Derived Antigens Are Not Necessarily Good Target Candidates: Enolase and ISG75 as Examples

et al. 2021

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Salivarian trypanosomes comprise a group of extracellular anthroponotic and zoonotic parasites. The only sustainable method for global control of these infection is through vaccination of livestock animals. Despite multiple reports describing promising laboratory results, no single field-applicable solution has been successful so far. Conventionally, vaccine research focusses mostly on exposed immunogenic antigens, or the structural molecular knowledge of surface exposed invariant immunogens. Unfortunately, extracellular parasites (or parasites with extracellular life stages) have devised efficient defense systems against host antibody attacks, so they can deal with the mammalian humoral immune response. In the case of trypanosomes, it appears that these mechanisms have been perfected, leading to vaccine failure in natural hosts. Here, we provide two examples of potential vaccine candidates that, despite being immunogenic and accessible to the immune system, failed to induce a functionally protective memory response. First, trypanosomal enolase was tested as a vaccine candidate, as it was recently characterized as a highly conserved enzyme that is readily recognized during infection by the host antibody response. Secondly, we re-addressed a vaccine approach towards the Invariant Surface Glycoprotein ISG75, and showed that despite being highly immunogenic, trypanosomes can avoid anti-ISG75 mediated parasitemia control.

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Trypanosoma evansi contains two auxiliary enzymes of glycolytic metabolism: Phosphoenolpyruvate carboxykinase and pyruvate phosphate dikinase

Cited by 7 publications

References 58 publications

Gluconeogenesis using glycerol as a substrate in bloodstream-form Trypanosoma brucei

Gluconeogenesis using glycerol as a substrate in bloodstream-form Trypanosoma brucei

Phosphoglycerate kinase: structural aspects and functions, with special emphasis on the enzyme from Kinetoplastea

The History of Anti-Trypanosome Vaccine Development Shows That Highly Immunogenic and Exposed Pathogen-Derived Antigens Are Not Necessarily Good Target Candidates: Enolase and ISG75 as Examples

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