A Squalene Epoxidase Is Involved in Biosynthesis of Both the Antitumor Compound Clavaric Acid and Sterols in the Basidiomycete H. sublateritium

Godio, Ramiro P.; Fouces, Roberto; Martı́n, Juan F.

doi:10.1016/j.chembiol.2007.10.018

Cited by 45 publications

(33 citation statements)

References 46 publications

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“…Squalene epoxidase can carry out two successive epoxidations, performing the mirror image epoxidations of both the 2,3 and 22,23 end positions of the squalene molecule. Di-epoxidation of squalene by squalene epoxidase has been reported in numerous triterpenoid synthase systems (25)(26)(27)(28)(29), and plant squalene epoxidases have been functionally expressed and shown to yield both mono-and di-oxidosqualene (30,31). Modeling of the SgSQE protein supports di-epoxidation and indicates that the presence of the first epoxy oxygen does not hinder the docking for the second epoxidation (SI Appendix, Fig.…”

Section: Resultsmentioning

confidence: 88%

The biosynthetic pathway of the nonsugar, high-intensity sweetener mogroside V from Siraitia grosvenorii

Itkin

Davidovich‐Rikanati

Cohen

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

152

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The consumption of sweeteners, natural as well as synthetic sugars, is implicated in an array of modern-day health problems. Therefore, natural nonsugar sweeteners are of increasing interest. We identify here the biosynthetic pathway of the sweet triterpenoid glycoside mogroside V, which has a sweetening strength of 250 times that of sucrose and is derived from mature fruit of luo-han-guo (Siraitia grosvenorii, monk fruit). A whole-genome sequencing of Siraitia, leading to a preliminary draft of the genome, was combined with an extensive transcriptomic analysis of developing fruit. A functional expression survey of nearly 200 candidate genes identified the members of the five enzyme families responsible for the synthesis of mogroside V: squalene epoxidases, triterpenoid synthases, epoxide hydrolases, cytochrome P450s, and UDP-glucosyltransferases. Protein modeling and docking studies corroborated the experimentally proven functional enzyme activities and indicated the order of the metabolic steps in the pathway. A comparison of the genomic organization and expression patterns of these Siraitia genes with the orthologs of other Cucurbitaceae implicates a strikingly coordinated expression of the pathway in the evolution of this species-specific and valuable metabolic pathway. The genomic organization of the pathway genes, syntenously preserved among the Cucurbitaceae, indicates, on the other hand, that gene clustering cannot account for this novel secondary metabolic pathway.

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Section: Resultsmentioning

confidence: 88%

The biosynthetic pathway of the nonsugar, high-intensity sweetener mogroside V from Siraitia grosvenorii

Itkin

Davidovich‐Rikanati

Cohen

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

152

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“…It was shown that the cyclization outcome of this enzyme (as for diterpene synthases, see above) can be readily altered; substitution of one amino acid residue was sufficient to direct cyclization either towards lanosterol or protostadienol [224]. Two genes, oxidosqualene synthase and squalene epoxidase, were identified in the antitumor clavaric acid producer Hypholoma sublaterium (a basidiomycete), and are expected to be required for the production of this secondary metabolite [225,226]. In an effort to elucidate the biosynthesis of lanosterane-type triterpenoids in Wolfiporia and Ganoderma, genomic and transcriptomic studies were published by several groups [227][228][229][230].…”

Section: Fungal Triterpenoid Biosynthesismentioning

confidence: 99%

Biosynthesis of Terpenoid Natural Products in Fungi

Schmidt‐Dannert

2014

Advances in Biochemical Engineering/Biotechnology

108

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Tens of thousands of terpenoid natural products have been isolated from plants and microbial sources. Higher fungi (Ascomycota and Basidiomycota) are known to produce an array of well-known terpenoid natural products, including mycotoxins, antibiotics, antitumor compounds, and phytohormones. Except for a few well-studied fungal biosynthetic pathways, the majority of genes and biosynthetic pathways responsible for the biosynthesis of a small number of these secondary metabolites have only been discovered and characterized in the past 5-10 years. This chapter provides a comprehensive overview of the current knowledge on fungal terpenoid biosynthesis from biochemical, genetic, and genomic viewpoints. Enzymes involved in synthesizing, transferring, and cyclizing the prenyl chains that form the hydrocarbon scaffolds of fungal terpenoid natural products are systematically discussed. Genomic information and functional evidence suggest differences between the terpenome of the two major fungal phyla--the Ascomycota and Basidiomycota--which will be illustrated for each group of terpenoid natural products.

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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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A Squalene Epoxidase Is Involved in Biosynthesis of Both the Antitumor Compound Clavaric Acid and Sterols in the Basidiomycete H. sublateritium

Cited by 45 publications

References 46 publications

The biosynthetic pathway of the nonsugar, high-intensity sweetener mogroside V from Siraitia grosvenorii

The biosynthetic pathway of the nonsugar, high-intensity sweetener mogroside V from Siraitia grosvenorii

Biosynthesis of Terpenoid Natural Products in Fungi

Squalene monooxygenase – a target for hypercholesterolemic therapy

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