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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

Molecular structures of cholesterol and ergosterol. The arrows indicate the parts of the molecules which have been shown to be essential for the growth of mammalian cells (cholesterol), fungi, and trypanosomatids (ergosterol and 24-methyl sterols).
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fig1: Molecular structures of cholesterol and ergosterol. The arrows indicate the parts of the molecules which have been shown to be essential for the growth of mammalian cells (cholesterol), fungi, and trypanosomatids (ergosterol and 24-methyl sterols).

Mentions: It is now well established that an important metabolic pathway in fungi and in members of the Trypanosomatidae family is the sterol biosynthesis (SB) pathway. In these organisms, this pathway produces a special class of sterols, including ergosterol and other 24-methyl sterols, that is, required for their growth and viability, but is absent from mammalian host cells [4, 5]. Cholesterol and ergosterol differ in a few minor ways, as shown in Figure 1; cholesterol has only one double bond (Δ5(6)) in the B ring and has a fully saturated side chain without a methyl group at C24. It has been shown that some parts of the sterol molecule are important for its activity in cellular membranes. In the tetracyclic nucleus, the 3β–OH is obligatory for growth, whereas the presence of methyl groups at C14 or C4 do not allow growth. These two characteristics are essential for both cholesterol and ergosterol to support growth. However, certain characteristics of ergosterol that are absent in the cholesterol molecule, such as the presence of two double bonds in the B ring of the steroid nucleus, the presence of a β methyl at position 24, and the double bond at C22 in the side chain are essential for the growth of fungi and trypanosomatids.


Sterol Biosynthesis Pathway as Target for Anti-trypanosomatid Drugs.

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

Molecular structures of cholesterol and ergosterol. The arrows indicate the parts of the molecules which have been shown to be essential for the growth of mammalian cells (cholesterol), fungi, and trypanosomatids (ergosterol and 24-methyl sterols).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig1: Molecular structures of cholesterol and ergosterol. The arrows indicate the parts of the molecules which have been shown to be essential for the growth of mammalian cells (cholesterol), fungi, and trypanosomatids (ergosterol and 24-methyl sterols).
Mentions: It is now well established that an important metabolic pathway in fungi and in members of the Trypanosomatidae family is the sterol biosynthesis (SB) pathway. In these organisms, this pathway produces a special class of sterols, including ergosterol and other 24-methyl sterols, that is, required for their growth and viability, but is absent from mammalian host cells [4, 5]. Cholesterol and ergosterol differ in a few minor ways, as shown in Figure 1; cholesterol has only one double bond (Δ5(6)) in the B ring and has a fully saturated side chain without a methyl group at C24. It has been shown that some parts of the sterol molecule are important for its activity in cellular membranes. In the tetracyclic nucleus, the 3β–OH is obligatory for growth, whereas the presence of methyl groups at C14 or C4 do not allow growth. These two characteristics are essential for both cholesterol and ergosterol to support growth. However, certain characteristics of ergosterol that are absent in the cholesterol molecule, such as the presence of two double bonds in the B ring of the steroid nucleus, the presence of a β methyl at position 24, and the double bond at C22 in the side chain are essential for the growth of fungi and trypanosomatids.

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