scholarly journals Leishmania Protein Kinases: Important Regulators of the Parasite Life Cycle and Molecular Targets for Treating Leishmaniasis

2021 ◽  
Vol 9 (4) ◽  
pp. 691
Author(s):  
Antonia Efstathiou ◽  
Despina Smirlis
Keyword(s):  
Life Cycle ◽  
Protein Kinases ◽  
Clinical Manifestations ◽  
Molecular Targets ◽  
Leishmania Infection ◽  
Mammalian Host ◽  
Insect Vector ◽  
Eukaryotic Protein ◽  
Wide Range ◽  
Eukaryotic Protein Kinases

Leishmania is a protozoan parasite of the trypanosomatid family, causing a wide range of diseases with different clinical manifestations including cutaneous, mucocutaneous and visceral leishmaniasis. According to WHO, one billion people are at risk of Leishmania infection as they live in endemic areas while there are 12 million infected people worldwide. Annually, 0.9–1.6 million new infections are reported and 20–50 thousand deaths occur due to Leishmania infection. As current chemotherapy for treating leishmaniasis exhibits numerous drawbacks and due to the lack of effective human vaccine, there is an urgent need to develop new antileishmanial therapy treatment. To this end, eukaryotic protein kinases can be ideal target candidates for rational drug design against leishmaniasis. Eukaryotic protein kinases mediate signal transduction through protein phosphorylation and their inhibition is anticipated to be disease modifying as they regulate all essential processes for Leishmania viability and completion of the parasitic life cycle including cell-cycle progression, differentiation and virulence. This review highlights existing knowledge concerning the exploitation of Leishmania protein kinases as molecular targets to treat leishmaniasis and the current knowledge of their role in the biology of Leishmania spp. and in the regulation of signalling events that promote parasite survival in the insect vector or the mammalian host.

scholarly journals Inhibitor of Cysteine Proteases Is Critical for Motility and Infectivity of Plasmodium Sporozoites

mBio ◽  
2013 ◽  
Vol 4 (6) ◽  
Author(s):  
Katja E. Boysen ◽  
Kai Matuschewski
Keyword(s):  
Life Cycle ◽  
Salivary Glands ◽  
Cysteine Proteases ◽  
Gliding Motility ◽  
Parasitic Infections ◽  
Mammalian Host ◽  
Insect Vector ◽  
Mosquito Vector ◽  
Infected Female ◽  
Wide Range

ABSTRACT Malaria is transmitted when motile sporozoites are injected into the dermis by an infected female Anopheles mosquito. Inside the mosquito vector, sporozoites egress from midgut-associated oocysts and eventually penetrate the acinar cells of salivary glands. Parasite-encoded factors with exclusive vital roles in the insect vector can be studied by classical reverse genetics. Here, we characterized the in vivo roles of Plasmodium berghei falstatin/ICP (inhibitor of cysteine proteases). This protein was previously suggested to act as a protease inhibitor during erythrocyte invasion. We show by targeted gene disruption that loss of ICP function does not affect growth inside the mammalian host but causes a complete defect in sporozoite transmission. Sporogony occurred normally in icp(−) parasites, but hemocoel sporozoites showed a defect in continuous gliding motility and infectivity for salivary glands, which are prerequisites for sporozoite transmission to the mammalian host. Absence of ICP correlates with enhanced cleavage of circumsporozoite protein, in agreement with a role as a protease regulator. We conclude that ICP is essential for only the final stages of sporozoite maturation inside the mosquito vector. This study is the first genetic evidence that an ICP is necessary for the productive motility of a eukaryotic parasitic cell. IMPORTANCE Cysteine proteases and their inhibitors are considered ideal drug targets for the treatment of a wide range of diseases, including cancer and parasitic infections. In protozoan parasites, including Leishmania, Trypanosoma, and Plasmodium, cysteine proteases play important roles in life cycle progression. A mouse malaria model provides an unprecedented opportunity to study the roles of a parasite-encoded inhibitor of cysteine proteases (ICP) over the entire parasite life cycle. By precise gene deletion, we found no evidence that ICP influences disease progression or parasite virulence. Instead, we discovered that this factor is necessary for parasite movement and malaria transmission from mosquitoes to mammals. This finding in a fast-moving unicellular protozoan has important implications for malaria intervention strategies and the roles of ICPs in the regulation of eukaryotic cell migration.

scholarly journals Metabolic reprogramming during the Trypanosoma brucei life cycle

F1000Research ◽  
2017 ◽  
Vol 6 ◽  
pp. 683 ◽  
Author(s):  
Terry K. Smith ◽  
Frédéric Bringaud ◽  
Derek P. Nolan ◽  
Luisa M. Figueiredo
Keyword(s):  
Life Cycle ◽  
Trypanosoma Brucei ◽  
Model Organism ◽  
Protozoan Parasite ◽  
Tsetse Fly ◽  
Metabolic Reprogramming ◽  
Mammalian Host ◽  
Insect Vector ◽  
Environmental Signals ◽  
Cellular Metabolic Activity

Cellular metabolic activity is a highly complex, dynamic, regulated process that is influenced by numerous factors, including extracellular environmental signals, nutrient availability and the physiological and developmental status of the cell. The causative agent of sleeping sickness, Trypanosoma brucei, is an exclusively extracellular protozoan parasite that encounters very different extracellular environments during its life cycle within the mammalian host and tsetse fly insect vector. In order to meet these challenges, there are significant alterations in the major energetic and metabolic pathways of these highly adaptable parasites. This review highlights some of these metabolic changes in this early divergent eukaryotic model organism.

scholarly journals Open Reading Frame sso2387 from the Archaeon Sulfolobus solfataricus Encodes a Polypeptide with Protein-Serine Kinase Activity

2003 ◽  
Vol 185 (11) ◽  
pp. 3436-3445 ◽  
Author(s):  
Brian H. Lower ◽  
Peter J. Kennelly
Keyword(s):  
Protein Kinases ◽  
Catalytic Domain ◽  
Sulfolobus Solfataricus ◽  
Open Reading Frame ◽  
Serine Kinase ◽  
Eukaryotic Protein Kinase ◽  
Reading Frame ◽  
Eukaryotic Protein ◽  
High Concentrations ◽  
Eukaryotic Protein Kinases

ABSTRACT The predicted polypeptide product of open reading frame sso2387 from the archaeon Sulfolobus solfataricus, SsoPK2, displayed several of the sequence features conserved among the members of the “eukaryotic” protein kinase superfamily. sso2387 was cloned, and its polypeptide product was expressed in Escherichia coli. The recombinant protein, rSsoPK2, was recovered in insoluble aggregates that could be dispersed by using high concentrations (5 M) of urea. The solubilized polypeptide displayed the ability to phosphorylate itself as well as several exogenous proteins, including mixed histones, casein, bovine serum albumin, and reduced carboxyamidomethylated and maleylated lysozyme, on serine residues. The source of this activity resided in that portion of the protein displaying homology to the catalytic domain of eukaryotic protein kinases. By use of mass spectrometry, the sites of autophosphorylation were found to be located in two areas, one immediately N terminal to the region corresponding to subdomain I of eukaryotic protein kinases, and the second N terminal to the presumed activation loop located between subdomains VII and VIII. Autophosphorylation of rSsoPK2 could be uncoupled from the phosphorylation of exogenous proteins by manipulation of the temperature or mutagenic alteration of the enzyme. Autophosphorylation was detected only at temperatures ≥60°C, whereas phosphorylation of exogenous proteins was detectable at 37°C. Similarly, replacement of one of the potential sites of autophosphorylation, Ser548, with alanine blocked autophosphorylation but not phosphorylation of an exogenous protein, casein.

scholarly journals The Landscape of Atypical and Eukaryotic Protein Kinases

2019 ◽  
Vol 40 (11) ◽  
pp. 818-832 ◽  
Author(s):  
Georgi K. Kanev ◽  
Chris de Graaf ◽  
Iwan J.P. de Esch ◽  
Rob Leurs ◽  
Thomas Würdinger ◽  
...  
Keyword(s):  
Protein Kinases ◽  
Eukaryotic Protein ◽  
Eukaryotic Protein Kinases

scholarly journals Expanding the archaellum regulatory network - the eukaryotic protein kinases ArnC and ArnD influence motility ofSulfolobus acidocaldarius

2016 ◽  
Vol 6 (1) ◽  
pp. e00414 ◽  
Author(s):  
Lena Hoffmann ◽  
Andreas Schummer ◽  
Julia Reimann ◽  
Maria F. Haurat ◽  
Amanda J. Wilson ◽  
...  
Keyword(s):  
Protein Kinases ◽  
Regulatory Network ◽  
Eukaryotic Protein ◽  
Eukaryotic Protein Kinases

scholarly journals An evolutionary perspective on the kinome of malaria parasites

2012 ◽  
Vol 367 (1602) ◽  
pp. 2607-2618 ◽  
Author(s):  
Eric Talevich ◽  
Andrew B. Tobin ◽  
Natarajan Kannan ◽  
Christian Doerig
Keyword(s):  
Protein Phosphorylation ◽  
Protein Kinases ◽  
Evolutionary Perspective ◽  
Malaria Parasites ◽  
Eukaryotic Protein ◽  
Independent Evolution ◽  
Ancient Lineage ◽  
Parasitic Lifestyle ◽  
Eukaryotic Protein Kinases

Malaria parasites belong to an ancient lineage that diverged very early from the main branch of eukaryotes. The approximately 90-member plasmodial kinome includes a majority of eukaryotic protein kinases that clearly cluster within the AGC, CMGC, TKL, CaMK and CK1 groups found in yeast, plants and mammals, testifying to the ancient ancestry of these families. However, several hundred millions years of independent evolution, and the specific pressures brought about by first a photosynthetic and then a parasitic lifestyle, led to the emergence of unique features in the plasmodial kinome. These include taxon-restricted kinase families, and unique peculiarities of individual enzymes even when they have homologues in other eukaryotes. Here, we merge essential aspects of all three malaria-related communications that were presented at the Evolution of Protein Phosphorylation meeting, and propose an integrated discussion of the specific features of the parasite's kinome and phosphoproteome.

The Structural Basis for Control of Eukaryotic Protein Kinases

2012 ◽  
Vol 81 (1) ◽  
pp. 587-613 ◽  
Author(s):  
Jane A. Endicott ◽  
Martin E.M. Noble ◽  
Louise N. Johnson
Keyword(s):  
Protein Kinases ◽  
Structural Basis ◽  
Eukaryotic Protein ◽  
Eukaryotic Protein Kinases
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