Drug Targets in Trypanosomal and Leishmanial Pentose Phosphate Pathway

Comini, Marcelo A.; Ortiz, Cecilia; Cazzulo, Juán José

doi:10.1002/9783527670383.ch16

Cited by 12 publications

(23 citation statements)

References 65 publications

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“…1) is the first enzyme of the oxidative branch of PPP, catalysing the oxidation of G6P to 6-phosphogluconolactone (6PGL) as NADP+ is reduced to NADPH (reviewed in [246]). This enzyme shares approximately 50% identity to its human homologue [247]. It localises mostly to the cytosol, although there is a small fraction compartimentalized in the glycosomes, although a typical peroxisomal targeting sequence (PTS) is absent [248,249].…”

Section: Oxidative Branchmentioning

confidence: 99%

“…Therefore, 6PGL may have a detrimental role to prevent the accumulation of this PPP intermediate. However, its essentiality has not been addressed in any trypanosomatid [247].…”

Section: Oxidative Branchmentioning

confidence: 99%

“…1), which is responsible for the oxidation and decarboxylation of 6-phosphogluconate (6PG) to Ru5P, while again reducing NADP+ to NADPH [255]. It has only around 35% homology to the human counterpart, however there is a high conservation of the residues involved in the substrate and coenzyme binding, challenging the design of selective inhibitors [247,256]. Similarly to the first two enzymes of the pathway, it localises predominantly to the cytosol, and to a less extent to the glycosomes [257].…”

Section: Oxidative Branchmentioning

confidence: 99%

“…This is probably exacerbated in vivo with the increase of G6P flow through the PPP. Moreover, it remains to be investigated Version: Postprint (identical content as published paper) This is a self-archived document from i3S -Instituto de Investigação e Inovação em Saúde in the University of Porto Open Repository For Open Access to more of our publications, please visit http://repositorio-aberto.up.pt/ A01/00 whether a decrease in R5P production also plays a role in the observed defect [247]. 6PGDH essentiality has not yet been addressed in Leishmania and T. cruzi.…”

Section: Oxidative Branchmentioning

confidence: 99%

“…In summary, the oxidative branch is therefore of critical importance to these parasites, as it supplies not only Ru5P, a precursor of the non-oxidative branch, but also NADPH, an essential molecule for lipid synthesis, defence against oxidative stress by regenerating GSH, among other important cellular processes [247].…”

Section: Oxidative Branchmentioning

confidence: 99%

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Potential Drug Targets in the Pentose Phosphate Pathway of Trypanosomatids

Loureiro

Faria

Smith

et al. 2019

CMC

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The trypanosomatids, Trypanosoma brucei, Trypanosoma cruzi and Leishmania spp, are causative agents of important human diseases such African sleeping sickness, Chagas' disease and Leishmaniasis, respectively. The high impact of these diseases on human health and economy worldwide, the unsatisfactory available chemotherapeutic options and the absence of human effective vaccines, strongly justifies the search for new drugs. The pentose phosphate pathway has been proposed to be a viable strategy to defeat several infectious diseases, including those from trypanosomatids, as it includes an oxidative branch, important in the maintenance of cell redox homeostasis, and a non-oxidative branch in which ribose 5-phosphate and erythrose 4-phosphate, precursors of nucleic acids and aromatic amino acids, are produced. This review provides an overview of the available chemotherapeutic options against these diseases and discusses the potential of genetically validated enzymes from the pentose phosphate pathway of trypanosomatids to be explored as potential drug targets.

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Section: Oxidative Branchmentioning

confidence: 99%

“…Therefore, 6PGL may have a detrimental role to prevent the accumulation of this PPP intermediate. However, its essentiality has not been addressed in any trypanosomatid [247].…”

Section: Oxidative Branchmentioning

confidence: 99%

Section: Oxidative Branchmentioning

confidence: 99%

Section: Oxidative Branchmentioning

confidence: 99%

Section: Oxidative Branchmentioning

confidence: 99%

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Potential Drug Targets in the Pentose Phosphate Pathway of Trypanosomatids

Loureiro

Faria

Smith

et al. 2019

CMC

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Molecular explorations of the Leishmania donovani 6-phosphogluconolactonase enzyme, a key player in the pentose phosphate pathway

Dhumal

Kumar²,

Paul³

et al. 2022

Biochimie

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Crystal structure of Leishmania donovani glucose 6-phosphate dehydrogenase reveals a unique N-terminal domain

et al. 2022

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Since unicellular parasites highly depend on NADPH as a source for reducing equivalents, the pentose phosphate pathway, especially the first and rate-limiting NADPH-producing enzyme glucose 6-phosphate dehydrogenase (G6PD), is considered an excellent antitrypanosomatid drug target. Here we present the crystal structure of Leishmania donovani G6PD (LdG6PD) elucidating the unique N-terminal domain of Kinetoplastida G6PDs. Our investigations on the function of the N-domain suggest its involvement in the formation of a tetramer that is completely different from related Trypanosoma G6PDs. Structural and functional investigations further provide interesting insights into the binding mode of LdG6PD, following an ordered mechanism, which is confirmed by a G6P-induced domain shift and rotation of the helical N-domain. Taken together, these insights into LdG6PD contribute to the understanding of G6PDs’ molecular mechanisms and provide an excellent basis for further drug discovery approaches.

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Drug Targets in Trypanosomal and Leishmanial Pentose Phosphate Pathway

Cited by 12 publications

References 65 publications

Potential Drug Targets in the Pentose Phosphate Pathway of Trypanosomatids

Potential Drug Targets in the Pentose Phosphate Pathway of Trypanosomatids

Molecular explorations of the Leishmania donovani 6-phosphogluconolactonase enzyme, a key player in the pentose phosphate pathway

Crystal structure of Leishmania donovani glucose 6-phosphate dehydrogenase reveals a unique N-terminal domain

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