The Biosynthesis of Ergosterol

Mercer, Eric

doi:10.1002/ps.2780150206

Cited by 116 publications

(53 citation statements)

References 148 publications

(6 reference statements)

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“…When Prototheca was fed 100 mg of [met) nine per 300 ml of medium, a weak mas trideuterated ergosterol (MT, 399) and a stri trum of trideuterated protothecasterol was ot These results, coupled with the detection of c Prototheca, indicated Prototheca by C-24 alkylation is stabilized by a 1,2-hydride shift from 1j,_~Xn H-27 to C-25 rather than H-24 to C-25 as is the case in yeast (40) [methyl-2H3]methionine (800 ,tg/ml). As shown in Fig.…”

Section: Resultsmentioning

confidence: 95%

Sterol phylogenesis and algal evolution.

Nes¹,

Norton²,

Crumley³

et al. 1990

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

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The stereochemistry of several sterol precursors and end products synthesized by two fungal-like microorganisms Prototheca wickerhamii (I) and Dictyostelium discoideum (H) have been determined by chromatographic (TLC, GLC, and HPLC) and spectral (UV, MS,-and 'H NMR) methods. From I and H the following sterols were isolated from the cells : cycloartenol, cyclolaudenol, 24(28)-methylenecycloartanol, ergosterol, protothecasterol, 4a-methylergostanol, 4a-methylclionastanol, clionastanol, 2413-ethylcholesta-8,22-enol, and dictyosterol. In addition, the mechanism of C-24 methylation was investigated in both organisms by feeding to I[2-3H]lanosterol, [2-3H] Based on what is known in the literature regarding sterol distribution and phylogenesis together with our rmdings that the stereochemical outcome of squalene oxide cyclization leads to the production of cycloartenol rather than lanosterol (characteristic of the fungal genealogy) and the chirality of the C-24 alkyl group is similar in the two nonphotosynthetic microbes (Ji oriented), we conclude that Prototheca is an apoplastic Chlorelia (i.e., an alga) and that Dictyostelium as well as the other soil amoebae that synthesize cycloartenol evolved from algal rather than fungal ancestors.The sterol pathway is thought to be very ancient, perhaps having arisen during the later stages of prokaryote evolution (1, 2). True sterols-e.g., end products such as cholesterolare antedated by the production of sterol-like compoundse.g., pentacyclic triterpenoids (3-6)-which were formed in the Precambrian anaerobic environment by the cyclization of squalene. Once molecular oxygen was in sufficient quantity in the atmosphere to permit squalene oxide genesis, a switching mechanism became operative to divert squalene from pentacyclic triterpenoid production to sterol synthesis (6, 7). The first compounds derived by the anaerobic cyclization of squalene oxide are the tetracyclic stereoisomers cycloartenol and lanosterol. Neither stereoisomer is known to be formed by cyclization in the same organism, whether the latter is a prokaryote or a eukaryote (2). This bifurcation in the sterol pathway is now recognized in biochemical textbooks (8-10) and in reviews on evolution (11-13) as a means to dissociate groups of organisms with an evolutionary history of oxygenic photosynthesis-e.g., as detected through the stereospecific formation of cycloartenol and its further metabolism of the 96,19-cyclopropyl ring-from those nonphotosynthetic progenitors and their descendants, which possess a lanosterolbased pathway (2). The association of the cycloartenol route and the endosymbiotic origin and subsequent loss of the chloroplast in some nonphotosynthetic systems is not clear. The biosynthesis of cycloartenol occurs in microsomes (14) and proceeds when the chloroplast is absent (15-18). In neither case is the biosynthesis of the stereoisomer influenced by the structure of the functional steroid at the end of the pathway, and their occurrence is not influenced by the molecular clock or mutatio...

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Section: Resultsmentioning

confidence: 95%

Sterol phylogenesis and algal evolution.

Nes¹,

Norton²,

Crumley³

et al. 1990

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

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“…Others have observed lower levels of ergosterol [I 8], but this may have been due to harvesting cells in stationary phase where we have observed a similar effect. The accumulation of obtusifolione following azole treatment in C. neoformans indicates interference with the process of C4 demethylation where the last step involves a ketosteroid reductase [19]. Interference with this step may be due to a direct effect of azole, or more likely, inhibition caused by retention of the 14a-methyl group in the substrate as appears to occur for S. cerevisiae during attempted A 5"6 desaturation [8].…”

Section: Discussionmentioning

confidence: 99%

Resistant P45051A1 activity in azole antifungal tolerant Cryptococcus neoformans from AIDS patients

et al. 1995

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“…The predominant sterol of the yeast Saccharomyces cerevisiae is ergosterol, which is structurally and functionally related to cholesterol of mammalian cells. Yeast enzymes catalyzing the transformation of squalene, the polyisoprene precursor, to ergosterol are also believed to be microsomal proteins (Mercer, 1984;Pal-tauf et al, 1992), but the precise subcellular localization has not yet been described.…”

Section: Introductionmentioning

confidence: 99%

Dual Localization of Squalene Epoxidase, Erg1p, in Yeast Reflects a Relationship between the Endoplasmic Reticulum and Lipid Particles

Leber

Landl

Zinser

et al. 1998

MBoC

180

136

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Squalene epoxidase, encoded by the ERG1 gene in yeast, is a key enzyme of sterol biosynthesis. Analysis of subcellular fractions revealed that squalene epoxidase was present in the microsomal fraction (30,000 ϫ g) and also cofractionated with lipid particles. A dual localization of Erg1p was confirmed by immunofluorescence microscopy. On the basis of the distribution of marker proteins, 62% of cellular Erg1p could be assigned to the endoplasmic reticulum and 38% to lipid particles in late logarithmicphase cells. In contrast, sterol ⌬ 24 -methyltransferase (Erg6p), an enzyme catalyzing a late step in sterol biosynthesis, was found mainly in lipid particles cofractionating with triacylglycerols and steryl esters. The relative distribution of Erg1p between the endoplasmic reticulum and lipid particles changes during growth. Squalene epoxidase (Erg1p) was absent in an erg1 disruptant strain and was induced fivefold in lipid particles and in the endoplasmic reticulum when the ERG1 gene was overexpressed from a multicopy plasmid. The amount of squalene epoxidase in both compartments was also induced approximately fivefold by treatment of yeast cells with terbinafine, an inhibitor of the fungal squalene epoxidase. In contrast to the distribution of the protein, enzymatic activity of squalene epoxidase was only detectable in the endoplasmic reticulum but was absent from isolated lipid particles. When lipid particles of the wild-type strain and microsomes of an erg1 disruptant were mixed, squalene epoxidase activity was partially restored. These findings suggest that factor(s) present in the endoplasmic reticulum are required for squalene epoxidase activity. Close contact between lipid particles and endoplasmic reticulum may be necessary for a concerted action of these two compartments in sterol biosynthesis.

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The Biosynthesis of Ergosterol

Cited by 116 publications

References 148 publications

Sterol phylogenesis and algal evolution.

Sterol phylogenesis and algal evolution.

Resistant P45051A1 activity in azole antifungal tolerant Cryptococcus neoformans from AIDS patients

Dual Localization of Squalene Epoxidase, Erg1p, in Yeast Reflects a Relationship between the Endoplasmic Reticulum and Lipid Particles

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