Sterol Biosynthesis by a Prokaryote: First<i>in Vitro</i>Identification of the Genes Encoding Squalene Epoxidase and Lanosterol Synthase from<i>Methylococcus capsulatus</i>

Summary• Triterpenes are one of the largest classes of plant metabolites and have important functions. A diverse array of triterpenoid skeletons are synthesized via the isoprenoid pathway by enzymatic cyclization of 2,3-oxidosqualene. The genomes of the lower plants Chlamydomonas reinhardtii and moss (Physcomitrella patens) contain just one oxidosqualene cyclase (OSC) gene (for sterol biosynthesis), whereas the genomes of higher plants contain nine to 16 OSC genes.• Here we carry out functional analysis of rice OSCs and rigorous phylogenetic analysis of 96 OSCs from higher plants, including Arabidopsis thaliana, Oryza sativa, Sorghum bicolor and Brachypodium distachyon.• The functional analysis identified an amino acid sequence for isoarborinol synthase (OsIAS) (encoded by Os11g35710 ⁄ OsOSC11) in rice. Our phylogenetic analysis suggests that expansion of OSC members in higher plants has occurred mainly through tandem duplication followed by positive selection and diversifying evolution, and consolidated the previous suggestion that dicot triterpene synthases have been derived from an ancestral lanosterol synthase instead of directly from their cycloartenol synthases.• The phylogenetic trees are consistent with the reaction mechanisms of the protosteryl and dammarenyl cations which parent a wide variety of triterpene skeletal types, allowing us to predict the functions of the uncharacterized OSCs.

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“…, 2003; Lamb et al. , 2007; Nakano et al. , 2007), although hopane cyclase is the dominant form in most bacteria.…”

Section: Discussionmentioning

confidence: 99%

Divergent evolution of oxidosqualene cyclases in plants

et al. 2011

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“…99,100 Moreover, the cycloartenol and lanosterol synthases have been cloned and functionally expressed from the same bacterium Stigmatella aurantiaca , and the lanosterol synthase has been cloned from other primitive organisms, including Methylococcus capsulatus and Gemmata obscruiglobus. (101−104)…”

Section: Recent Advances In Sterol Biosynthesismentioning

confidence: 99%

Biosynthesis of Cholesterol and Other Sterols

2011

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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 ). Several years of investigations aimed at fi nding inhibitors of pathogenic fungi SE resulted in numerous antimycotics [e.g., terbinafi ne (Ryder , 1989 )], which are stiil in clinical use today (Berg and Plempel , 1989 ).…”

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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Sterol Biosynthesis by a Prokaryote: Firstin VitroIdentification of the Genes Encoding Squalene Epoxidase and Lanosterol Synthase fromMethylococcus capsulatus

Cited by 25 publications

References 24 publications

Divergent evolution of oxidosqualene cyclases in plants

Divergent evolution of oxidosqualene cyclases in plants

Biosynthesis of Cholesterol and Other Sterols

Squalene monooxygenase – a target for hypercholesterolemic therapy

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