Characterization of quinonoid-Dihydropteridine Reductase (QDPR) from the Lower Eukaryote Leishmania major

Lye, Lon-Fye; Cunningham, Mark L.; Beverley, Stephen M.

doi:10.1074/jbc.m206543200

Cited by 30 publications

(30 citation statements)

References 72 publications

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“…1A), which, given the lability of dihydropterins, seems likely also to be mitochondrial. q-Dihydropterin reductases in mammals, protists, and certain bacteria belong to the large and diverse short chain dehydrogenase-reductase family (Lye et al, 2002;Wilquet et al, 2004). Although Arabidopsis has some 86 short chain dehydrogenasereductase proteins, only eight have predicted mitochondrial targeting peptides, and none of the eight yet has a known function (Noiriel et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

Phylogenomic and Functional Analysis of Pterin-4a-Carbinolamine Dehydratase Family (COG2154) Proteins in Plants and Microorganisms

et al. 2008

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Pterin-4a-carbinolamine dehydratases (PCDs) recycle oxidized pterin cofactors generated by aromatic amino acid hydroxylases (AAHs). PCDs are known biochemically only from animals and one bacterium, but PCD-like proteins (COG2154 in the Clusters of Orthologous Groups [COGs] database) are encoded by many plant and microbial genomes. Because these genomes often encode no AAH homologs, the annotation of their COG2154 proteins as PCDs is questionable. Moreover, some COG2154 proteins lack canonical residues that are catalytically important in mammalian PCDs. Diverse COG2154 proteins of plant, fungal, protistan, and prokaryotic origin were therefore tested for PCD activity by functional complementation in Escherichia coli, and the plant proteins were localized using green fluorescent protein fusions. Higher and lower plants proved to have two COG2154 proteins, a mitochondrial one with PCD activity and a noncanonical, plastidial one without. Phylogenetic analysis indicated that the latter is unique to plants and arose from the former early in the plant lineage. All 10 microbial COG2154 proteins tested had PCD activity; six of these came from genomes with no AAH, and six were noncanonical. The results suggested the motif [EDKH]-x(3)-H-[HN]-[PCS]-x(5,6)-[YWF]-x(9)-[HW]-x(8,15)-D as a signature for PCD activity. Organisms having a functional PCD but no AAH partner include angiosperms, yeast, and various prokaryotes. In these cases, PCD presumably has another function. An ancillary role in molybdopterin cofactor metabolism, hypothesized from phylogenomic evidence, was supported by demonstrating significantly lowered activities of two molybdoenzymes in Arabidopsis thaliana PCD knockout mutants. Besides this role, we propose that partnerless PCDs support the function of as yet unrecognized pterin-dependent enzymes.

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Section: Discussionmentioning

confidence: 99%

Phylogenomic and Functional Analysis of Pterin-4a-Carbinolamine Dehydratase Family (COG2154) Proteins in Plants and Microorganisms

et al. 2008

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“…Next, we studied the quinonoid dihydropteridine reductase (QDPR) gene, a gene whose high levels throughout the parasite infectious cycle may contribute to virulence (22). It has been suggested that parasite QDPR may be a useful target for chemotherapy (23). These data prompted us to measure QDPR gene expression after treatment with 2b and 4b.…”

Section: New Leishmanicidal Drugsmentioning

confidence: 99%

Leishmanicidal Activities of Novel Methylseleno-Imidocarbamates

Fernández-Rubio

Campbell

Vacas

et al. 2015

Antimicrob Agents Chemother

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fThe generation of new antileishmanial drugs has become a priority. Selenium and its derivatives stand out as having promising leishmanicidal activity. In fact, some parasites express selenoproteins and metabolize selenium. Recently, selenium derivatives have shown the potential to reduce parasitemia, clinical manifestations, and mortality in parasite-infected mice. In this paper, after selecting four candidates according to drug similarity parameters, we observed that two of them, called compounds 2b [methyl-N,N=-di(thien-2-ylcarbonyl)-imidoselenocarbamate] and 4b [methyl-N,N=-di(5-nitrothien-3-ylcarbonyl)-imidoselenocarbamate], exhibit low 50% inhibitory concentrations (IC 50 s) (<3 M) and good selectivity indexes (SIs) (>5) in Leishmania major promastigotes and lack toxicity on macrophages. In addition, in analysis of their therapeutic potential against L. major in vitro infection, both compounds display a dramatic reduction of amastigote burden (ϳ80%) with sublethal concentrations. Furthermore, in macrophages, these selenocompounds induce nitric oxide production, which has been described to be critical for defense against intracellular pathogens. Compounds 2b and 4b were demonstrated to cause cell cycle arrest in G 1 . Interestingly, evaluation of expression of genes related to proliferation (PCNA), treatment resistance (ABC transporter and alpha-tubulin), and virulence (quinonoid dihydropteridine reductase [QDPR]) showed several alterations in gene expression profiling. All these results prompt us to propose both compounds as candidates to treat leishmanial infections.

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“…Furthermore, there is recycling of reduced pterins in Leishmania via the pterin-4␣-carbinolamine dehydratase (PCD). Therefore, this regeneration pathway of reduced pterins (15) can also be a target for intervention.…”

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confidence: 99%

In Silico Screening, Structure-Activity Relationship, and Biologic Evaluation of Selective Pteridine Reductase Inhibitors Targeting Visceral Leishmaniasis

Kaur

Kumar

Tyagi³

et al. 2011

Antimicrob Agents Chemother

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In this study we utilized the concept of rational drug design to identify novel compounds with optimal selectivity, efficacy and safety, which would bind to the target enzyme pteridine reductase 1 (PTR1) in Leishmania parasites. Twelve compounds afforded from Baylis-Hillman chemistry were docked by using the QUANTUM program into the active site of Leishmania donovani PTR1 homology model. The biological activity for these compounds was estimated in green fluorescent protein-transfected L. donovani promastigotes, and the most potential analogue was further investigated in intracellular amastigotes. Structure-activity relationship based on homology model drawn on our recombinant enzyme was substantiated by recombinant enzyme inhibition assay and growth of the cell culture.

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Characterization of quinonoid-Dihydropteridine Reductase (QDPR) from the Lower Eukaryote Leishmania major

Cited by 30 publications

References 72 publications

Phylogenomic and Functional Analysis of Pterin-4a-Carbinolamine Dehydratase Family (COG2154) Proteins in Plants and Microorganisms

Phylogenomic and Functional Analysis of Pterin-4a-Carbinolamine Dehydratase Family (COG2154) Proteins in Plants and Microorganisms

Leishmanicidal Activities of Novel Methylseleno-Imidocarbamates

In Silico Screening, Structure-Activity Relationship, and Biologic Evaluation of Selective Pteridine Reductase Inhibitors Targeting Visceral Leishmaniasis

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