Structural basis for the relaxed substrate selectivity of Leishmania mexicana broad specificity aminotransferase

Jiang, Wen; Nowicki, Cristina; Blankenfeldt, Wulf

doi:10.1016/j.molbiopara.2015.09.007

Cited by 3 publications

(2 citation statements)

References 29 publications

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“…This finding is similar to the results of Berg et al (17) using an L. donovani strain isolated in Ethiopia (MHOM/ET/67/HU3), where PMM r resulted in 14 metabolic changes compared to the metabolism of the WT, whereas MIL r induced 20 changes. A recent study found that PMM r was associated with increased glycolytic activity to form products that can scavenge hydrogen peroxide (26). However, the results from this study did not show any major changes in TCA cycle metabolites.…”

Section: Discussioncontrasting

confidence: 88%

Genomic and Metabolomic Polymorphism among Experimentally Selected Paromomycin-Resistant Leishmania donovani Strains

Shaw

Imamura

Downing

et al. 2019

Antimicrob Agents Chemother

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Understanding the mechanism(s) underpinning drug resistance could lead to novel treatments to reverse the increased tolerance of a pathogen. In this study, paromomycin (PMM) resistance (PMMr) was induced in three Nepalese clinical strains of Leishmania donovani with different inherent susceptibilities to antimony (Sb) drugs by stepwise exposure of promastigotes to PMM. Exposure to PMM resulted in the production of mixed populations of parasites, even though a single cloned population was used at the start of selection. PMM 50% inhibitory concentration (IC50) values for PMMr parasites varied between 104 and 481 μM at the promastigote stage and 32 and 195 μM at the intracellular amastigote stage. PMM resistance was associated with increased resistance to nitric oxide at the amastigote stage but not the promastigote stage (P < 0.05). This effect was most marked in the Sb-resistant (Sbr) PMMr clone, in which PMM resistance was associated with a significant upregulation of glutathione compared to that in its wild type (P < 0.05), although there was no change in the regulation of trypanothione (detected in its oxidized form). Interestingly, PMMr strains showed an increase in either the keto acid derivative of isoleucine (Sb intermediate PMMr) or the 2-hydroxy acids derived from arginine and tyrosine (Sb susceptible PMMr and Sbr PMMr). These results are consistent with the recent finding that the upregulation of the branched-chain amino acid aminotransferase and d-lactate dehydrogenase is linked to PMMr. In addition, we found that PMMr is associated with a significant increase in aneuploidy during PMM selection in all the strains, which could allow the rapid selection of genetic changes that confer a survival advantage.

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Section: Discussioncontrasting

confidence: 88%

Genomic and Metabolomic Polymorphism among Experimentally Selected Paromomycin-Resistant Leishmania donovani Strains

Shaw

Imamura

Downing

et al. 2019

Antimicrob Agents Chemother

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“…When only considering those genes with a copy number difference amplitude of at least 0.3 haploid genome copies, 11 genes could be identified, of which 6 have been annotated (i.e., ADP/ATP mitochondrial carrier-like protein, ras-related protein RAB1, 60S ribosomal protein L6 , proteasome regulatory non-ATP-ase subunit 3 , an RNA-binding protein and ribosomal protein L1a ). ADP/ATP mitochondrial carrier-like proteins are known to transfer molecules across mitochondrial membranes [ 47 ] and could therefore potentially play a role in drug transport into a main target organelle. The Ras-related protein RAB1 is involved in vesicular trafficking and is a known regulator of secretory pathways of several important Leishmania virulence factors, including gp63 and acid phosphatase [ 48 ].…”

Section: Discussionmentioning

confidence: 99%

Experimental Selection of Paromomycin Resistance in Leishmania donovani Amastigotes Induces Variable Genomic Polymorphisms

et al. 2021

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The relatively high post-treatment relapse rates of paromomycin (PMM) in visceral leishmaniasis treatment and the swift emergence of experimental drug resistance challenge its broad application and urge for rational use and monitoring of resistance. However, no causal molecular mechanisms to Leishmania PMM resistance have been identified so far. To gain insights into potential resistance mechanisms, twelve experimentally selected Leishmania donovani clonal lines and the non-cloned preselection population, with variable degrees of PMM resistance, were subjected to whole genome sequencing. To identify genomic variations potentially associated with resistance, SNPs, Indels, chromosomal somy and gene copy number variations were compared between the different parasite lines. A total of 11 short nucleotide variations and the copy number alterations in 39 genes were correlated to PMM resistance. Some of the identified genes are involved in transcription, translation and protein turn-over (transcription elongation factor-like protein, RNA-binding protein, ribosomal protein L1a, 60S ribosomal protein L6, eukaryotic translation initiation factor 4E-1, proteasome regulatory non-ATP-ase subunit 3), virulence (major surface protease gp63, protein-tyrosine phosphatase 1-like protein), mitochondrial function (ADP/ATP mitochondrial carrier-like protein), signaling (phosphatidylinositol 3-related kinase, protein kinase putative and protein-tyrosine phosphatase 1-like protein) and vesicular trafficking (ras-related protein RAB1). These results indicate that, in Leishmania, the aminoglycoside PMM affects protein translational processes and underlines the complex and probably multifactorial origin of resistance.

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Insights into the substrate specificity, structure, and dynamics of plant histidinol-phosphate aminotransferase (HISN6)

Rutkiewicz

Nogués

Witek

et al. 2023

Plant Physiology and Biochemistry

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Structural basis for the relaxed substrate selectivity of Leishmania mexicana broad specificity aminotransferase

Cited by 3 publications

References 29 publications

Genomic and Metabolomic Polymorphism among Experimentally Selected Paromomycin-Resistant Leishmania donovani Strains

Genomic and Metabolomic Polymorphism among Experimentally Selected Paromomycin-Resistant Leishmania donovani Strains

Experimental Selection of Paromomycin Resistance in Leishmania donovani Amastigotes Induces Variable Genomic Polymorphisms

Insights into the substrate specificity, structure, and dynamics of plant histidinol-phosphate aminotransferase (HISN6)

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