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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

Promastigotes treated with quinuclidine and azasterol, respectively, showing the presence of structures related with autophagy such as a large vacuole containing many membrane profiles ((a), arrowheads), and a myelin-like figures involving part of the cytosol ((b), arrowhead). Star indicates the presence of a possible contractile vacuole near the flagellar pocket. A, autophagosome; F, flagellum; K, kinetoplast; M, mitochondrion; N, nucleus. (a) This image is reproduced with permission from [66] Elsevier. Bars, 0.25 μm.
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fig8: Promastigotes treated with quinuclidine and azasterol, respectively, showing the presence of structures related with autophagy such as a large vacuole containing many membrane profiles ((a), arrowheads), and a myelin-like figures involving part of the cytosol ((b), arrowhead). Star indicates the presence of a possible contractile vacuole near the flagellar pocket. A, autophagosome; F, flagellum; K, kinetoplast; M, mitochondrion; N, nucleus. (a) This image is reproduced with permission from [66] Elsevier. Bars, 0.25 μm.

Mentions: Alterations in the nuclear membrane, Golgi complex and endoplasmic reticulum were also observed after treatment with different SB inhibitors (Figures 7(a)–7(c)). The presence of a multivesicular body associated with the trans-Golgi network can be seen in Figure 7(b) (star), thus suggesting alterations in the secretory pathway. Furthermore, Figure 7(c) (stars) also shows the presence of some vacuoles resembling autophagosomes, thus suggesting the occurrence of cell death by autophagy (reviewed in [86–88]). The presence of large vacuoles containing membrane profiles, endoplasmic reticulum forming myelin-like figures or engulfing a part of the cytoplasm, and damaged organelles supports the idea that an autophagy-like process takes place in these cells (Figures 8(a)-8(b)).


Sterol Biosynthesis Pathway as Target for Anti-trypanosomatid Drugs.

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

Promastigotes treated with quinuclidine and azasterol, respectively, showing the presence of structures related with autophagy such as a large vacuole containing many membrane profiles ((a), arrowheads), and a myelin-like figures involving part of the cytosol ((b), arrowhead). Star indicates the presence of a possible contractile vacuole near the flagellar pocket. A, autophagosome; F, flagellum; K, kinetoplast; M, mitochondrion; N, nucleus. (a) This image is reproduced with permission from [66] Elsevier. Bars, 0.25 μm.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig8: Promastigotes treated with quinuclidine and azasterol, respectively, showing the presence of structures related with autophagy such as a large vacuole containing many membrane profiles ((a), arrowheads), and a myelin-like figures involving part of the cytosol ((b), arrowhead). Star indicates the presence of a possible contractile vacuole near the flagellar pocket. A, autophagosome; F, flagellum; K, kinetoplast; M, mitochondrion; N, nucleus. (a) This image is reproduced with permission from [66] Elsevier. Bars, 0.25 μm.
Mentions: Alterations in the nuclear membrane, Golgi complex and endoplasmic reticulum were also observed after treatment with different SB inhibitors (Figures 7(a)–7(c)). The presence of a multivesicular body associated with the trans-Golgi network can be seen in Figure 7(b) (star), thus suggesting alterations in the secretory pathway. Furthermore, Figure 7(c) (stars) also shows the presence of some vacuoles resembling autophagosomes, thus suggesting the occurrence of cell death by autophagy (reviewed in [86–88]). The presence of large vacuoles containing membrane profiles, endoplasmic reticulum forming myelin-like figures or engulfing a part of the cytoplasm, and damaged organelles supports the idea that an autophagy-like process takes place in these cells (Figures 8(a)-8(b)).

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