Leishmania mexicana: Identification and characterization of an aspartyl proteinase activity

Valdivieso, Elizabeth; Dagger, Fracehuli; Rascón, Ana

doi:10.1016/j.exppara.2006.10.006

Cited by 44 publications

(29 citation statements)

References 27 publications

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“…These molecules have been identified as promising targets for the development of a rational antileishmanial chemotherapy (Coombs et al 2001;Klemba and Goldberg 2002;Mottram et al 2004;McKerrow et al 2008;McLuskey et al 2010). It is within this context that we reported the presence of aspartyl proteinase activity in promastigotes of Leishmania mexicana and Leishmania infantum (Valdivieso et al 2007(Valdivieso et al , 2010, which is sensitive to diazoacetyl-DL-norleucin methyl ester (DAN) and the specific HIV aspartyl proteinase inhibitors, Ac-Leu-Val-Phenylalaninal, Nelfinavir (NFV), and Saquinavir (Valdivieso et al 2010). Santos et al (2009) also reports the inhibition by NFV and Lopinavir of certain hydrolytic activity from a Leishmania amazonensis extract on an HIV-1 protease substrate, which supports the hypothesis that these drugs have a direct effect on the aspartyl proteinase activity of Leishmania sp.…”

Section: Introductionmentioning

confidence: 64%

“…Santos et al (2009) also reports the inhibition by NFV and Lopinavir of certain hydrolytic activity from a Leishmania amazonensis extract on an HIV-1 protease substrate, which supports the hypothesis that these drugs have a direct effect on the aspartyl proteinase activity of Leishmania sp. In addition, we found that in the presence of aspartyl proteinase inhibitors, promastigotes and amastigotes of L. mexicana and L. infantum show antiproliferative activity with a significant percentage of binucleate cells, and in some cases multinucleate cells, indicating a blockage of cytokinesis (Valdivieso et al 2007(Valdivieso et al , 2010, and reiterating the importance of aspartyl proteinase activity for the survival of these trypanosomatids. To date, two aspartyl proteinase genes have been identified within the genome of Leishmania sp.…”

Section: Introductionmentioning

confidence: 87%

“…The presence of aspartyl proteinases in protozoa from the Trypanosomatidae family was only postulated less than a decade ago (Valdivieso et al 2007;Pinho et al 2009;Santos et al 2009), leading to the suggestion that they may play a role in the proliferation of the Leishmania parasites (Valdivieso et al 2007;Santos et al 2009;Valdivieso et al 2010;White et al 2011a). In the present study, we cloned the full L. major sequence of a molecule that belongs to a Leishmania family of proteins that include an active RP domain, characteristic of the aspartyl proteases from the family A 2 .…”

Section: Discussionmentioning

confidence: 99%

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Ddi1-like protein from Leishmania major is an active aspartyl proteinase

Perteguer

Gómez‐Puertas

Cañavate

et al. 2013

Cell Stress and Chaperones

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Eukaryotic cells respond to DNA damage by activating damage checkpoint pathways, which arrest cell cycle progression and induce gene expression. We isolated a full-length cDNA encoding a 49-kDa protein from Leishmania major, which exhibited significant deduced amino acid sequence homology with the annotated Leishmania sp. DNA damage-inducible (Ddi1-like) protein, as well as with the Ddi1 protein from Saccharomyces cerevisiae. In contrast to the previously described Ddi1 protein, the protein from L. major displays three domains: (1) an NH2-terminal ubiquitin like; (2) a COOH terminal ubiquitinassociated; (3) a retroviral aspartyl proteinase, containing the typical D[S/T]G signature. The function of the L. major Ddi1-like recombinant protein was investigated after expression in baculovirus/insect cells and biochemical analysis, revealing preferential substrate selectivity for aspartyl proteinase A 2 family substrates, with optimal activity in acidic conditions. The proteolytic activity was inhibited by aspartyl proteinase inhibitors. Molecular modeling of the retroviral domain of the Ddi1-like Leishmania protein revealed a dimer structure that contained a double AspSer-Gly-Ala amino acid sequence motif, in an almost identical geometry to the exhibited by the homologous retroviral aspartyl protease domain of yeast Ddi1 protein. Our results indicate that the isolated Ddi1-like protein is a functional aspartyl proteinase in L. major, opening possibility to be considered as a potential target for novel antiparasitic drugs.

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Section: Introductionmentioning

confidence: 64%

Section: Introductionmentioning

confidence: 87%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Ddi1-like protein from Leishmania major is an active aspartyl proteinase

Perteguer

Gómez‐Puertas

Cañavate

et al. 2013

Cell Stress and Chaperones

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“…However, the incidence of HIV-Leishmania co-infections has been decreasing since the introduction of HAART, in which aspartic-type protease inhibitors were included [94,95] . These findings instigated the research to confirm the possible connection between aspartic protease expression and basic molecular processes in Leishmania [96][97][98][99][100][101][102][103] . Our group showed that HIV protease inhibitors were able to impair in vitro proliferation of L. amazonensis promastigotes in a dose-dependent manner and in different extensions, in which nelfinavir (IC50 = 15.1 ± 1.1 μmol/L), lopinavir (IC50 = 16.5 ± 0.8 μmol/L) and amprenavir (IC50 = 62.0 ± 2.1 μmol/L) were the most potent compounds [103] .…”

Section: F Pedrosoimentioning

confidence: 99%

Protease expression by microorganisms and its relevance to crucial physiological/pathological events

Santos¹

2011

WJBC

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The treatment of infections caused by fungi and trypanosomatids is difficult due to the eukaryotic nature of these microbial cells, which are similar in several biochemical and genetic aspects to host cells. Aggravating this scenario, very few antifungal and anti-trypanosomatidal agents are in clinical use and, therefore, therapy is limited by drug safety considerations and their narrow spectrum of activity, efficacy and resistance. The search for new bioactive agents against fungi and trypanosomatids has been expanded because progress in biochemistry and molecular biology has led to a better understanding of important and essential pathways in these microorganisms including nutrition, growth, proliferation, signaling, differentiation and death. In this context, proteolytic enzymes produced by these eukaryotic microorganisms are appointed and, in some cases, proven to be excellent targets for searching novel natural and/or synthetic pharmacological compounds, in order to cure or prevent invasive fungal/trypanosomatid diseases. With this task in mind, our research group and others have focused on aspartic-type proteases, since the activity of this class of hydrolytic enzymes is directly implicated in several facets of basic biological processes of both fungal and trypanosomatid cells as well as due to the participation in numerous events of interaction between these microorganisms and host structures. In the present paper, a concise revision of the beneficial effects of aspartic protease inhibitors, with emphasis on the aspartic protease inhibitors used in the anti-human immunodeficiency virus therapy, will be presented and discussed using our experience with the following microbial models: the yeast Candida albicans , the filamentous fungus Fonsecaea pedrosoi and the protozoan trypanosomatid Leishmania amazonensis .

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“…Alves and co-workers showed that metallo, serine and aspartic peptidase activities are down-regulated during the shock-induced transformation of promastigotes into amastigotes, by the hydrolysis of specific chromogenic substrates. Later, Valdivieso et al [192] reported the presence of an enzyme capable of degrading the synthetic substrate benzoyl-Arg-Gly-Phe-Phe-Leu-4-methoxy--naphthyl-amide, which is selective for cathepsin D like aspartic peptidases. Diazo-acetyl-norleucinemethylester (DAN) not only inhibited the enzyme activity but also interfered in parasite growth in culture.…”

Section: Aspartic Peptidasesmentioning

confidence: 99%

Biological Roles of Peptidases in Trypanosomatids~!2009-11-26~!2010-02-15~!2010-03-18~!

Vermelho

Branquinha²,

d’Avila-Levy³

et al. 2010

TOPARAJ

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Abstract:In this review, we report the recent developments in the characterization of peptidases and their possible biological functions in the Trypanosomatidae family. The focus will be on peptidases from Trypanosoma cruzi, Leishmania spp., African trypanosomes and plant and insect trypanosomatids. There are numerous events in parasite development where the involvement of peptidases has been established, and they will be approached in the present review. Also in this review we will discuss the central roles have been proposed for peptidases in diverse processes such as virulence, host cell interaction and invasion, catabolism of host proteins, differentiation, cell cycle progression and both stimulation and evasion of host immune responses.

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Leishmania mexicana: Identification and characterization of an aspartyl proteinase activity

Cited by 44 publications

References 27 publications

Ddi1-like protein from Leishmania major is an active aspartyl proteinase

Ddi1-like protein from Leishmania major is an active aspartyl proteinase

Protease expression by microorganisms and its relevance to crucial physiological/pathological events

Biological Roles of Peptidases in Trypanosomatids~!2009-11-26~!2010-02-15~!2010-03-18~!

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