Umbelliferone aminoalkyl derivatives as inhibitors of human oxidosqualene-lanosterol cyclase

Oliaro‐Bosso, Simonetta; Taramino, Silvia; Viola, Franca; Tagliapietra, Silvia; Ermondi, Giuseppe; Cravotto, Giancarlo; Balliano, Gianni

doi:10.1080/14756360802318688

Cited by 12 publications

(6 citation statements)

References 32 publications

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“…idosqualene cyclase (Erg7p) activity [47][48]. In absence of mitochondrial DNA, the Erg7p enzyme is correctly associated with LDs and not delocalized.…”

Section: Accepted Manuscriptmentioning

confidence: 99%

Ergosterol reduction impairs mitochondrial DNA maintenance in S. cerevisiae

Cirigliano

Macone

Bianchi

et al. 2019

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

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Sterols are essential lipids, involved in many biological processes. In Saccharomyces cerevisiae, the enzymes of the ergosterol biosynthetic pathway (Erg proteins) are localised in different cellular compartments. With the aim of studying organelle interactions, we discovered that Erg27p resides mainly in Lipid Droplets (LDs) in respiratory competent cells, while in absence of respiration, is found mostly in the ER. The results presented in this paper demonstrate an interplay between the mitochondrial respiration and ergosterol production: on the one hand, rho° cells show lower ergosterol content when compared with wild type respiratory competent cells, on the other hand, the ergosterol biosynthetic pathway influences the mitochondrial status, since treatment with ketoconazole, which blocks the ergosterol pathway, or the absence of the ERG27 gene, induced rho° production in S. cerevisiae. The loss of mitochondrial DNA in the ∆erg27 strain is fully suppressed by exogenous addition of ergosterol. These data suggest the notion that ergosterol is essential for maintaining the mitochondrial DNA attached to the inner mitochondrial membrane.

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“…idosqualene cyclase (Erg7p) activity [47][48]. In absence of mitochondrial DNA, the Erg7p enzyme is correctly associated with LDs and not delocalized.…”

Section: Accepted Manuscriptmentioning

confidence: 99%

Ergosterol reduction impairs mitochondrial DNA maintenance in S. cerevisiae

Cirigliano

Macone

Bianchi

et al. 2019

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

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“…Cell-free homogenates were obtained as described [38]. Briefly, after lysis of the cell wall with lyticase, the spheroplasts were homogenized with a Potter device.…”

Section: Enzyme Assaysmentioning

confidence: 99%

“…OSC activity was assayed as described [38]. Briefly, the homogenates were incubated with labeled [ 14 C]-(3S)-2,3-oxidosqualene (1000 cpm).…”

Section: Enzyme Assaysmentioning

confidence: 99%

Aminopropylindenes derived from Grundmann's ketone as a novel chemotype of oxidosqualene cyclase inhibitors

Lange

Keller

Müller

et al. 2013

European Journal of Medicinal Chemistry

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A series of aminopropylindenes, designed as mimics of a cationic high energy intermediate in the oxidosqualene cyclase(1) (OSC)-mediated cyclization of 2,3-oxidosqualen to lanosterol was prepared from Grundmann's ketone. Screening on OSCs from five different organisms revealed interesting activities and selectivities of some of the compounds. A N,N-dimethylaminopropyl derivative showed promising inhibition of Trypanosoma cruzi OSC in combination with low cytotoxicity, and showed significant reduction of cholesterol biosynthesis in a human cell line.

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“…In both yeast and mammalian cells, grown aerobically in the presence of radiolabeled acetate, a large amount of ergosterol/cholesterol accumulates, whereas a small amount of oxidosqualene and a negligible amount of dioxidosqualene forms [15,23,24]. The accumulation of oxidosqualenes (mainly dioxidosqualene), is indicative of reduced oxidosqualene cyclase functionality [19,25].…”

Section: Resultsmentioning

confidence: 99%

Divergent interactions involving the oxidosqualene cyclase and the steroid-3-ketoreductase in the sterol biosynthetic pathway of mammals and yeasts

Taramino

Teske

Oliaro‐Bosso

et al. 2010

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

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SummaryIn mammals and yeasts, oxidosqualene cyclase (OSC) catalyzes the formation of lanosterol, the first cyclic intermediate in sterol biosynthesis. We used a murine myeloma cell line (NS0), deficient in the 17β-hydroxysteroid dehydrogenase type 7 (HSD17B7), as a model to study the potential interaction of the HSD17B7 with the OSC in mammals. HSD17B7 is the orthologue of the yeast steroid-3-ketoreductase (ERG27), an enzyme of ergosterol biosynthesis that plays a protective role towards OSC. Tracer experiments with NS0 cells showed that OSC is fully active in these mammalian cells, suggesting that in mammals the ketosteroid reductase is not required for OSC activity. Mouse and human HSD17B7 were overexpressed in ERG27-deletant yeast cells, and recombinant strains were tested for (i) the ability to grow on different media, (ii) steroid-3-ketoreductase activity, and (iii) OSC activity. Recombinant strains grew more slowly than the control yeast ERG27-overexpressing strain on sterol-deficient media, whereas the growth rate was normal on media supplemented with a 3-ketoreductase substrate. The full enzymatic functionality of mammalian steroid-3-ketoreductase expressed in yeast along with the lack of (yeast) OSC activity point to an inability of the mammalian reductase to assist yeast OSC. Results demonstrate that in mammals, unlike in yeast, OSC and steroid-3-ketoreductase are non-interacting proteins.

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Umbelliferone aminoalkyl derivatives as inhibitors of human oxidosqualene-lanosterol cyclase

Cited by 12 publications

References 32 publications

Ergosterol reduction impairs mitochondrial DNA maintenance in S. cerevisiae

Ergosterol reduction impairs mitochondrial DNA maintenance in S. cerevisiae

Aminopropylindenes derived from Grundmann's ketone as a novel chemotype of oxidosqualene cyclase inhibitors

Divergent interactions involving the oxidosqualene cyclase and the steroid-3-ketoreductase in the sterol biosynthetic pathway of mammals and yeasts

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