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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

(a) Diferential interference contrast (DIC) microscopy  and (b) transmission electron microscopy  showing the presence of a prominent contractile vacuole (arrows) near the flagellar pocket after treatment of L. amazonensis promastigotes with quinuclidine inhibitors. In the left panel it is possible to observe a rounded and swollen parasite that probably indicates osmotic changes due alterations in the plasma membrane's permeability. F, flagellum; K, kinetoplast. Bars, 5 μm and 0.5 μm, respectively.
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fig9: (a) Diferential interference contrast (DIC) microscopy and (b) transmission electron microscopy showing the presence of a prominent contractile vacuole (arrows) near the flagellar pocket after treatment of L. amazonensis promastigotes with quinuclidine inhibitors. In the left panel it is possible to observe a rounded and swollen parasite that probably indicates osmotic changes due alterations in the plasma membrane's permeability. F, flagellum; K, kinetoplast. Bars, 5 μm and 0.5 μm, respectively.

Mentions: Recent studies using various microscopy techniques have shown that trypanosomatids possess a structure located close to the flagellar pocket identified as a contractile vacuole (reviewed in [89]). This structure became much more evident in L. amazonensis (Figures 9(a)-9(b)) and T. cruzi epimastigotes [64] treated with SB inhibitors. As observed by differential interference contrast microscopy, the treated cells appeared rounded and swollen (Figure 9(a)), suggesting osmotic changes, thus explaining the presence of a prominent contractile vacuole. These changes may be due to alterations in the plasma membrane's permeability to ions induced by the complete depletion of sterols and sterol-like molecules, which is likely to lead to significant changes of the physicochemical properties of the lipid bilayer [90].


Sterol Biosynthesis Pathway as Target for Anti-trypanosomatid Drugs.

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

(a) Diferential interference contrast (DIC) microscopy  and (b) transmission electron microscopy  showing the presence of a prominent contractile vacuole (arrows) near the flagellar pocket after treatment of L. amazonensis promastigotes with quinuclidine inhibitors. In the left panel it is possible to observe a rounded and swollen parasite that probably indicates osmotic changes due alterations in the plasma membrane's permeability. F, flagellum; K, kinetoplast. Bars, 5 μm and 0.5 μm, respectively.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig9: (a) Diferential interference contrast (DIC) microscopy and (b) transmission electron microscopy showing the presence of a prominent contractile vacuole (arrows) near the flagellar pocket after treatment of L. amazonensis promastigotes with quinuclidine inhibitors. In the left panel it is possible to observe a rounded and swollen parasite that probably indicates osmotic changes due alterations in the plasma membrane's permeability. F, flagellum; K, kinetoplast. Bars, 5 μm and 0.5 μm, respectively.
Mentions: Recent studies using various microscopy techniques have shown that trypanosomatids possess a structure located close to the flagellar pocket identified as a contractile vacuole (reviewed in [89]). This structure became much more evident in L. amazonensis (Figures 9(a)-9(b)) and T. cruzi epimastigotes [64] treated with SB inhibitors. As observed by differential interference contrast microscopy, the treated cells appeared rounded and swollen (Figure 9(a)), suggesting osmotic changes, thus explaining the presence of a prominent contractile vacuole. These changes may be due to alterations in the plasma membrane's permeability to ions induced by the complete depletion of sterols and sterol-like molecules, which is likely to lead to significant changes of the physicochemical properties of the lipid bilayer [90].

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