Different secreted phosphatase activities in<i>Leishmania amazonensis</i>

Fernandes, Arlete; Soares, Deivid Costa; Saraiva, Elvira M.; Meyer‐Fernandes, José Roberto; Souto-Padrón, Thaïs

doi:10.1111/1574-6968.12080

Cited by 34 publications

(32 citation statements)

References 48 publications

(67 reference statements)

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“…Phosphatases can be characterized on the basis of their location in the cell, which can be intracellular i.e., secreted to the extracellular medium from the cell or membrane bound i.e., associated to plasma membrane [34, 35]. Phosphatases were found to be widely distributed throughout the cell (cytoplasm, mitochondria, nucleus, extracellular, plasma membrane, etc.).…”

Section: Resultsmentioning

confidence: 99%

Deep Insight into the Phosphatomes of Parasitic Protozoa and a Web Resource ProtozPhosDB

Anwar¹,

Gourinath²

2016

PLoS ONE

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Phosphorylation dynamically regulates the function of proteins by maintaining a balance between protein kinase and phosphatase activity. A comprehensive understanding of the role phosphatases in cellular signaling is lacking in case of protozoans of medical and veterinary importance worldwide. The drugs used to treat protozoal diseases have many undesired effects and the development of resistance, highlights the need for new effective and safer antiprotozoal agents. In the present study we have analyzed phosphatomes of 15 protozoans of medical significance. We identified ~2000 phosphatases, out of which 21% are uncharacterized proteins. A significant positive correlation between phosphatome and proteome size was observed except for E. histolytica, having highest density of phosphatases irrespective of its proteome size. A difference in the number of phosphatases among different genera shows the variation in the signaling pathways they are involved in. The phosphatome of parasites is dominated by ser/thr phosphatases contrary to the vertebrate host dominated by tyrosine phosphatases. Phosphatases were widely distributed throughout the cell suggesting physiological adaptation of the parasite to regulate its host. 20% to 45% phosphatome of different protozoa consists of ectophosphatases, i.e. crucial for the survival of parasites. A database and a webserver “ProtozPhosDB” can be used to explore the phosphatomes of protozoans of medical significance.

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Section: Resultsmentioning

confidence: 99%

Deep Insight into the Phosphatomes of Parasitic Protozoa and a Web Resource ProtozPhosDB

Anwar¹,

Gourinath²

2016

PLoS ONE

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“…By combining our experimental results with sequence similarity searches and alignments of PLD_SC with other enzymes, we have identified other species of enzymes with similar amino acid sequence to that of PLD_SC that may also be inhibited by this class of molecules and that have physiological relevance as a drug target. The literature searches revealed that several of the potential new targets identified are also active or activated as membrane associated enzymes (like PLD_SC) at both the cell membrane and as part of intercellular vesicle transport pathways . Previous studies with these enzymes provides compelling functional evidence that kinetic and binding studies done with PLD_SC (Table , Figures.…”

Section: Discussionmentioning

confidence: 99%

Identifying New Drug Targets for Potent Phospholipase D Inhibitors: Combining Sequence Alignment, Molecular Docking, and Enzyme Activity/Binding Assays

et al. 2016

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Phospholipase D enzymes cleave phospholipid substrates generating choline and phosphatidic acid. Phospholipase D from Streptomyces chromofuscus is a non-HKD (histidine, lysine, and aspartic acid) phospholipase D as the enzyme is more similar to members of the diverse family of metallo-phosphodiesterase/phosphatase enzymes than phospholipase D enzymes with active site HKD repeats. A highly efficient library of phospholipase D inhibitors based on 1,3-disubstituted-4-amino-pyrazolopyrimidine core structure was utilized to evaluate the inhibition of purified S. chromofuscus phospholipase D. The molecules exhibited inhibition of phospholipase D activity (IC50 ) in the nanomolar range with monomeric substrate diC4 PC and micromolar range with phospholipid micelles and vesicles. Binding studies with vesicle substrate and phospholipase D strongly indicate that these inhibitors directly block enzyme vesicle binding. Following these compelling results as a starting point, sequence searches and alignments with S. chromofuscus phospholipase D have identified potential new drug targets. Using AutoDock, inhibitors were docked into the enzymes selected from sequence searches and alignments (when 3D co-ordinates were available) and results analyzed to develop next-generation inhibitors for new targets. In vitro enzyme activity assays with several human phosphatases demonstrated that the predictive protocol was accurate. The strategy of combining sequence comparison, docking, and high-throughput screening assays has helped to identify new drug targets and provided some insight into how to make potential inhibitors more specific to desired targets.

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“…Phosphatases can also be classifi ed according to their subcellular location, which can be intracellular (Andrews and Stark 2000 ;Zhan et al 2000 ); secreted from the cell to extracellular medium (Rodrigues et al 1999 ;Dutra et al 2001 ;Fernandes et al 2013 ); or even membrane-bound enzymes, which may be associated to plasma membranes . In this context, the ecto-phosphatases are surface membrane-bound proteins, whose active site faces the extracellular medium (Furuya et al 1998 ).…”

Section: Subcellular Localizationmentioning

confidence: 99%

“…Membrane-bound and secreted kinase and phosphatase activities are directly involved with the degree of virulence in pathogenic microorganisms (Cunningham 2002 ;Fernandes et al 2013 ). In L. donovani , it was observed that ecto-phosphatase activity was signifi cantly higher in virulent strains than in avirulent strains, suggesting that ecto-phosphatase may be considered as virulence marker (Singla et al 1992 ).…”

Section: Ecto-phosphatases As Virulence Markers: Possible Roles In Admentioning

confidence: 99%

Ecto-nucleotidases and Ecto-phosphatases from Leishmania and Trypanosoma Parasites

Freitas-Mesquita

Meyer‐Fernandes

2013

Subcellular Biochemistry

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Ecto-enzymes can be defined as membrane-bound proteins that have their active site facing the extracellular millieu. In trypanosomatids, the physiological roles of these enzymes remain to be completed elucidated; however, many important events have already been related to them, such as the survival of parasites during their complex life cycle and the successful establishment of host infection. This chapter focuses on two remarkable classes of ecto-enzymes: ecto-nucleotidases and ecto-phosphatases, summarizing their occurrence and possible physiological roles in Leishmania and Trypanosoma genera. Ecto-nucleotidases are characterized by their ability to hydrolyze extracellular nucleotides, playing an important role in purinergic signaling. By the action of these ecto-enzymes, parasites are capable of modulating the host immune system, which leads to a successful parasite infection. Furthermore, ecto-nucleotidases are also involved in the purine salvage pathway, acting in the generation of nucleosides that are able to cross plasma membrane via specialized transporters. Another important ecto-enzyme present in a vast number of pathogenic organisms is the ecto-phosphatase. These enzymes are able to hydrolyze extracellular phosphorylated substrates, releasing free inorganic phosphate that can be internalized by the cell, crossing the plasma membrane through a Pi-transporter. Ecto-phosphatases are also involved in the invasion and survival of parasite in the host cells. Several alternative functions have been suggested for these enzymes in parasites, such as participation in their proliferation, differentiation, nutrition and protection. In this context, the present chapter provides an overview of recent discoveries related to the occurrence of ecto-nucleotidase and ecto-phosphatase activities in Leishmania and Trypanosoma parasites.

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Different secreted phosphatase activities inLeishmania amazonensis

Cited by 34 publications

References 48 publications

Deep Insight into the Phosphatomes of Parasitic Protozoa and a Web Resource ProtozPhosDB

Deep Insight into the Phosphatomes of Parasitic Protozoa and a Web Resource ProtozPhosDB

Identifying New Drug Targets for Potent Phospholipase D Inhibitors: Combining Sequence Alignment, Molecular Docking, and Enzyme Activity/Binding Assays

Ecto-nucleotidases and Ecto-phosphatases from Leishmania and Trypanosoma Parasites

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