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Sterol Biosynthesis Pathway as Target for Anti-trypanosomatid Drugs.

de Souza W, Rodrigues JC - Interdiscip Perspect Infect Dis (2009)

Bottom Line: In this review, we analyze the effects of drugs such as (a) statins, which act on the mevalonate pathway by inhibiting HMG-CoA reductase, (b) bisphosphonates, which interfere with the isoprenoid pathway in the step catalyzed by farnesyl diphosphate synthase, (c) zaragozic acids and quinuclidines, inhibitors of squalene synthase (SQS), which catalyzes the first committed step in sterol biosynthesis, (d) allylamines, inhibitors of squalene epoxidase, (e) azoles, which inhibit C14alpha-demethylase, and (f) azasterols, which inhibit Delta(24(25))-sterol methyltransferase (SMT).Inhibition of this last step appears to have high selectivity for fungi and trypanosomatids, since this enzyme is not found in mammalian cells.Probably as a consequence of these primary effects, other important changes take place in the organization of the kinetoplast DNA network and on the protozoan cell cycle.

View Article: PubMed Central - PubMed

Affiliation: Laboratório de Ultraestrutura Celular Hertha Meyer, Instituto de Biofísicia Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, CCS-Bloco G, 21941-902, Rio de Janeiro, RJ, Brazil.

ABSTRACT
Sterols are constituents of the cellular membranes that are essential for their normal structure and function. In mammalian cells, cholesterol is the main sterol found in the various membranes. However, other sterols predominate in eukaryotic microorganisms such as fungi and protozoa. It is now well established that an important metabolic pathway in fungi and in members of the Trypanosomatidae family is one that produces a special class of sterols, including ergosterol, and other 24-methyl sterols, which are required for parasitic growth and viability, but are absent from mammalian host cells. Currently, there are several drugs that interfere with sterol biosynthesis (SB) that are in use to treat diseases such as high cholesterol in humans and fungal infections. In this review, we analyze the effects of drugs such as (a) statins, which act on the mevalonate pathway by inhibiting HMG-CoA reductase, (b) bisphosphonates, which interfere with the isoprenoid pathway in the step catalyzed by farnesyl diphosphate synthase, (c) zaragozic acids and quinuclidines, inhibitors of squalene synthase (SQS), which catalyzes the first committed step in sterol biosynthesis, (d) allylamines, inhibitors of squalene epoxidase, (e) azoles, which inhibit C14alpha-demethylase, and (f) azasterols, which inhibit Delta(24(25))-sterol methyltransferase (SMT). Inhibition of this last step appears to have high selectivity for fungi and trypanosomatids, since this enzyme is not found in mammalian cells. We review here the IC50 values of these various inhibitors, their effects on the growth of trypanosomatids (both in axenic cultures and in cell cultures), and their effects on protozoan structural organization (as evaluted by light and electron microscopy) and lipid composition. The results show that the mitochondrial membrane as well as the membrane lining the protozoan cell body and flagellum are the main targets. Probably as a consequence of these primary effects, other important changes take place in the organization of the kinetoplast DNA network and on the protozoan cell cycle. In addition, apoptosis-like and autophagic processes induced by several of the inhibitors tested led to parasite death.

No MeSH data available.


Related in: MedlinePlus

DIC microscopy (left panel) and immunofluorescence microcospy (right panel) of L. amazonensis promastigotes control (a)-(b) and treated with ER-119884 (c)-(d). The labeling corresponds to the cytoskeleton constituted mainly by tubulin, revelead here by using of an Alexa 488-labeled secondary antibody. The black arrow in DIC image corresponds to the cell body which sometimes appeared changed and rounded as compared to the control parasites, while the white arrows point to several tubulin clusters that accumulated in the cytosol after treatment. All images are reproduced with permission from [37] American Society for Microbiology. Bars, 5 μm.
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Related In: Results  -  Collection


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fig12: DIC microscopy (left panel) and immunofluorescence microcospy (right panel) of L. amazonensis promastigotes control (a)-(b) and treated with ER-119884 (c)-(d). The labeling corresponds to the cytoskeleton constituted mainly by tubulin, revelead here by using of an Alexa 488-labeled secondary antibody. The black arrow in DIC image corresponds to the cell body which sometimes appeared changed and rounded as compared to the control parasites, while the white arrows point to several tubulin clusters that accumulated in the cytosol after treatment. All images are reproduced with permission from [37] American Society for Microbiology. Bars, 5 μm.

Mentions: It is well known that in trypanosomatids there is a close connection between the plasma membrane lining the cell body and the subpellicular microtubules, and that the spatial distribution of these microtubules is responsible for the maintenance of the protozoan's shape (reviewed in [95]). Immunofluorescence microscopy of tubulin-stained trypanosomes treated with an SBI revealed changes in the shape of the cell and in the distribution of the subpellicular microtubules, probably due to alterations in the sterol composition of the plasma membrane [37]. Figures 12(a)–12(d) show the effect of ER-119884, an SQS inhibitor, on the cytoskeleton of L. amazonensis promastigotes. The changes were also seen by transmission electron microscopy (Figure 11(d)).


Sterol Biosynthesis Pathway as Target for Anti-trypanosomatid Drugs.

de Souza W, Rodrigues JC - Interdiscip Perspect Infect Dis (2009)

DIC microscopy (left panel) and immunofluorescence microcospy (right panel) of L. amazonensis promastigotes control (a)-(b) and treated with ER-119884 (c)-(d). The labeling corresponds to the cytoskeleton constituted mainly by tubulin, revelead here by using of an Alexa 488-labeled secondary antibody. The black arrow in DIC image corresponds to the cell body which sometimes appeared changed and rounded as compared to the control parasites, while the white arrows point to several tubulin clusters that accumulated in the cytosol after treatment. All images are reproduced with permission from [37] American Society for Microbiology. Bars, 5 μm.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2721973&req=5

fig12: DIC microscopy (left panel) and immunofluorescence microcospy (right panel) of L. amazonensis promastigotes control (a)-(b) and treated with ER-119884 (c)-(d). The labeling corresponds to the cytoskeleton constituted mainly by tubulin, revelead here by using of an Alexa 488-labeled secondary antibody. The black arrow in DIC image corresponds to the cell body which sometimes appeared changed and rounded as compared to the control parasites, while the white arrows point to several tubulin clusters that accumulated in the cytosol after treatment. All images are reproduced with permission from [37] American Society for Microbiology. Bars, 5 μm.
Mentions: It is well known that in trypanosomatids there is a close connection between the plasma membrane lining the cell body and the subpellicular microtubules, and that the spatial distribution of these microtubules is responsible for the maintenance of the protozoan's shape (reviewed in [95]). Immunofluorescence microscopy of tubulin-stained trypanosomes treated with an SBI revealed changes in the shape of the cell and in the distribution of the subpellicular microtubules, probably due to alterations in the sterol composition of the plasma membrane [37]. Figures 12(a)–12(d) show the effect of ER-119884, an SQS inhibitor, on the cytoskeleton of L. amazonensis promastigotes. The changes were also seen by transmission electron microscopy (Figure 11(d)).

Bottom Line: In this review, we analyze the effects of drugs such as (a) statins, which act on the mevalonate pathway by inhibiting HMG-CoA reductase, (b) bisphosphonates, which interfere with the isoprenoid pathway in the step catalyzed by farnesyl diphosphate synthase, (c) zaragozic acids and quinuclidines, inhibitors of squalene synthase (SQS), which catalyzes the first committed step in sterol biosynthesis, (d) allylamines, inhibitors of squalene epoxidase, (e) azoles, which inhibit C14alpha-demethylase, and (f) azasterols, which inhibit Delta(24(25))-sterol methyltransferase (SMT).Inhibition of this last step appears to have high selectivity for fungi and trypanosomatids, since this enzyme is not found in mammalian cells.Probably as a consequence of these primary effects, other important changes take place in the organization of the kinetoplast DNA network and on the protozoan cell cycle.

View Article: PubMed Central - PubMed

Affiliation: Laboratório de Ultraestrutura Celular Hertha Meyer, Instituto de Biofísicia Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, CCS-Bloco G, 21941-902, Rio de Janeiro, RJ, Brazil.

ABSTRACT
Sterols are constituents of the cellular membranes that are essential for their normal structure and function. In mammalian cells, cholesterol is the main sterol found in the various membranes. However, other sterols predominate in eukaryotic microorganisms such as fungi and protozoa. It is now well established that an important metabolic pathway in fungi and in members of the Trypanosomatidae family is one that produces a special class of sterols, including ergosterol, and other 24-methyl sterols, which are required for parasitic growth and viability, but are absent from mammalian host cells. Currently, there are several drugs that interfere with sterol biosynthesis (SB) that are in use to treat diseases such as high cholesterol in humans and fungal infections. In this review, we analyze the effects of drugs such as (a) statins, which act on the mevalonate pathway by inhibiting HMG-CoA reductase, (b) bisphosphonates, which interfere with the isoprenoid pathway in the step catalyzed by farnesyl diphosphate synthase, (c) zaragozic acids and quinuclidines, inhibitors of squalene synthase (SQS), which catalyzes the first committed step in sterol biosynthesis, (d) allylamines, inhibitors of squalene epoxidase, (e) azoles, which inhibit C14alpha-demethylase, and (f) azasterols, which inhibit Delta(24(25))-sterol methyltransferase (SMT). Inhibition of this last step appears to have high selectivity for fungi and trypanosomatids, since this enzyme is not found in mammalian cells. We review here the IC50 values of these various inhibitors, their effects on the growth of trypanosomatids (both in axenic cultures and in cell cultures), and their effects on protozoan structural organization (as evaluted by light and electron microscopy) and lipid composition. The results show that the mitochondrial membrane as well as the membrane lining the protozoan cell body and flagellum are the main targets. Probably as a consequence of these primary effects, other important changes take place in the organization of the kinetoplast DNA network and on the protozoan cell cycle. In addition, apoptosis-like and autophagic processes induced by several of the inhibitors tested led to parasite death.

No MeSH data available.


Related in: MedlinePlus