Allylamine Derivatives: New Class of Synthetic Antifungal Agents Inhibiting Fungal Squalene Epoxidase

Petrányi, G; Ryder, Neil S.; Stütz, Anton

doi:10.1126/science.6547247

Cited by 410 publications

(167 citation statements)

References 12 publications

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“…A similar effect has been described in Acerpseudoplatanus tissue culture cells treated with the sterol biosynthesis inhibitor compactin (Ryder & Goad, 1980). The residual biosynthesis in C. albicans was most probably due to methylation of sterol originating from precursors distal to squalene epoxidase, the primary point of inhibition by the allylamines (Ryder, 1984;Petranyi et al, 1984). This is supported by the earlier finding that ergosterol precursors disappear from C. albicans cells treated with a growth-inhibiting concentration of naftifine.…”

Section: Allylamines and Sterol C-24 Methylation I601supporting

confidence: 77%

Effect of Allylamine Antimycotic Agents on Fungal Sterol Biosynthesis Measured by Sterol Side-chain Methylation

Ryder

1985

Microbiology

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Sterol side-chain (C-24) methylation was assayed by incorporation of radioactivity from [Me-'T]methionine into the ergosterol fraction in cells of the pathogenic fungi Candida albicans, Candida parapsilosis and Trichophyton mentagrophytes. Methylation at C-24 occurred after nuclear demethylation in all cases. The method was used to measure ergosterol biosynthesis inhibition by the allylamine antimycotics naftifine and S F 86-327, which are known to block squalene epoxidation. In C. albicans cells treated with SF 86-327 (1 mg 1-I) to fully inhibit squalene epoxidation, C-24 methylation continued for several hours at about 40% of the control rate. This residual biosynthesis was probably due to methylation of endogenous sterol precursors. The degree of residual biosynthesis in the three fungi correlated well with their susceptibility to SF 86-327. The highly susceptible dermatophyte T. mentagrophytes had negligible residual sterol biosynthesis. These differences were not due to inhibition of methionine uptake. For naftifine (100 mg 1 -l ) there was evidence of a second inhibitory action in C. albicuns. A cell-free assay indicated that this was due to direct inhibition of the C-24 met hyltransferase.

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Section: Allylamines and Sterol C-24 Methylation I601supporting

confidence: 77%

Effect of Allylamine Antimycotic Agents on Fungal Sterol Biosynthesis Measured by Sterol Side-chain Methylation

Ryder

1985

Microbiology

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“…Migration was likely to be only partially disrupted in these 'lipid-deficient' embryos because we were unable to further reduce the function of these enzymes without interfering with the many diverse developmental processes and basic cellular functions that require the products of Hmgcrb and Fntb activities. Interestingly, we also found that the inhibition of Protein geranylgeranyltransferase 1b (Pggt1b) and Squalene epoxidase (Sqle) activities (Petranyi et al, 1984;Vasudevan et al, 1999) partially blocked FBMN migration (see Fig. S2 in the supplementary material), suggesting that both geranylgeranyl protein modification and cholesterol synthesis are required during this process.…”

Section: Research Articlementioning

confidence: 84%

Zebrafish Prickle1b mediates facial branchiomotor neuron migration via a farnesylation-dependent nuclear activity

et al. 2011

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SUMMARYThe facial branchiomotor neurons (FBMNs) undergo a characteristic tangential migration in the vertebrate hindbrain. We previously used a morpholino knockdown approach to reveal that zebrafish prickle1b (pk1b) is required for this migration. Here we report that FBMN migration is also blocked in a pk1b mutant with a disruption in the consensus farnesylation motif. We confirmed that this lipid modification is required during FBMN migration by disrupting the function of farnesyl biosynthetic enzymes. Furthermore, farnesylation of a tagged Pk1b is required for its nuclear localization. Using a unique rescue approach, we have demonstrated that Pk1b nuclear localization and farnesylation are required during FBMN migration. Our data suggest that Pk1b acts at least partially independently of core planar cell polarity molecules at the plasma membrane, and might instead be acting at the nucleus. We also found that the neuronal transcriptional silencer REST is necessary for FBMN migration, and we provide evidence that interaction between Pk1b and REST is required during this process. Finally, we demonstrate that REST protein, which is normally localized in the nuclei of migrating FBMNs, is depleted from the nuclei of Pk1b-deficient neurons. We conclude that farnesylation-dependent nuclear localization of Pk1b is required to regulate REST localization and thus FBMN migration.

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“…Then it was discovered in fungi as an enzyme taking part in ergosterol synthesis and in plants, where it is a part of phytosterols synthesis pathways (Petranyi et al , 1984 ;Godio et al , 2007 ;Rasbery et al , 2007 ;Uchida et al , 2007 ;He et al , 2008;Han et al , 2010 ). SE was also identifi ed in some bacteria which produce pentacyclic triterpens instead of sterols, so-called hopanoids synthesized from squalene by squalene-hopene cyclase (SHC) (EC 5.4.99.17) (Nakano et al, 2003;Pearson et al , 2003 ;Volkman , 2003 ;Nakano et al , 2007 ).…”

Section: Introduction: Squalene Monooxygenasementioning

confidence: 99%

Squalene monooxygenase – a target for hypercholesterolemic therapy

Belter¹,

Skupińska²,

Giel-Pietraszuk

et al. 2011

BCHM

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Squalene monooxygenase catalyzes the epoxidation of C-C double bond of squalene to yield 2,3-oxidosqualene, the key step of sterol biosynthesis pathways in eukaryotes. Sterols are essential compounds of these organisms and squalene epoxidation is an important regulatory point in their synthesis. Squalene monooxygenase downregulation in vertebrates and fungi decreases synthesis of cholesterol and ergosterol, respectively, which makes squalene monooxygenase a potent and attractive target of hypercholesterolemia and antifungal therapies. Currently some fungal squalene monooxygenase inhibitors (terbinafi ne, naftifi ne, butenafi ne) are in clinical use, whereas mammalian enzymes ' inhibitors are still under investigation. Research on new squalene monooxygenase inhibitors is important due to the prevalence of hypercholesterolemia and the lack of both suffi cient and safe remedies. In this paper we (i) review data on activity and the structure of squalene monooxygenase, (ii) present its inhibitors, (iii) compare current strategies of lowering cholesterol level in blood with some of the most promising strategies, (iv) underline advantages of squalene monooxygenase as a target for hypercholesterolemia therapy, and (v) discuss safety concerns about hypercholesterolemia therapy based on inhibition of cellular cholesterol biosynthesis and potential usage of squalene monooxygenase inhibitors in clinical practice. After many years of use of statins there is some clinical evidence for their adverse effects and only partial effectiveness. Currently they are drugs of choice but are used with many restrictions, especially in case of children, elderly patients and women of childbearing potential. Certainly, for the next few years, statins will continue to be a suitable tool for cost-effective cardiovascular prevention; however research on new hypolipidemic drugs is highly desirable. We suggest that squalene monooxygenase inhibitors could become the hypocholesterolemic agents of the future.

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Allylamine Derivatives: New Class of Synthetic Antifungal Agents Inhibiting Fungal Squalene Epoxidase

Cited by 410 publications

References 12 publications

Effect of Allylamine Antimycotic Agents on Fungal Sterol Biosynthesis Measured by Sterol Side-chain Methylation

Effect of Allylamine Antimycotic Agents on Fungal Sterol Biosynthesis Measured by Sterol Side-chain Methylation

Zebrafish Prickle1b mediates facial branchiomotor neuron migration via a farnesylation-dependent nuclear activity

Squalene monooxygenase – a target for hypercholesterolemic therapy

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