(1978). Metabolism of Sterols in Yeast. CRC Critical Reviews in Microbiology: Vol. 6, No. 4, pp. 301-341.

Metabolism of sterols in yeast.

Revisited after 50 Years: The `Stereochemical Interpretation of the Biogenetic Isoprene Rule for the Triterpenes'

The 2,3-oxido squalene (SO) cyclases represent a group of enzymes which convert SO into polycyclic triterpenoids such as lanosterol, cycloartenol, cucurbitadienol and beta-amyrin Taking into account the postulated model of the enzymatic cyclization of SO, we have investigated the possibility of designing compounds that would be selective and potent inhibitors of SO cyclases Due to the fundamental role of sterols in animal, higher plant and fungal tissues, these inhibitors might behave as very selective (ipocholesterolemic, antifungal or phytotoxic) drugs Our first approach was the synthesis and biological evaluation of 2-aza-2,3-dihydrosqualene and its derivatives which, being protonated at physiological pH, would present some similarities to the C-2 carbon ion generated by the opening of the oxirane ring of SO Microsomes from different sources (germinated pea cotyledons, maize seedlings, rat liver and yeasts) were utilized to determine the inhibition values (I50: concentration of inhibitor producing 50% inhibition at a given substrate concentration) From the results obtained so far we conclude that 2-aza-2-dihydrosqualene and its derivatives strongly inhibited the cyclases, the site of the enzyme responsible for binding to the inhibitor is quite sensitive to the steric hindrance, and the degree of the inhibitory activity is greater in higher plants than in rat liver or fungi

The squalene-2,3-epoxide cyclase as a model for the development of new drugs

Ergosta-5,7,24(28)-trien-3β-ol (trienol)6 was isolated from the intracellular symbiotes (symbiotic microorganisms) of the planthoppers,Nilaparvata lugens andLaodelphax striatellus. The steroidogenic end product of the symbiotes was found to depend on the environmental conditions, i.e., although trienol6 was produced under symbiotic conditions, ergosterol4 was formed in aerobic culture. When the normal diet was replaced by a steroiddeficient artificial one, the ratio of 24-methylenecholesterol5 to total insect sterols was significantly increased. The above study offers further corroborating evidence for our assumption that the host insects require 24-methylenecholesterol5 as an alternate source for cholesterol1 under certain environmental conditions. In our previous biotransformation experiments, 24methylenecholesterol5 was shown to be an immediate precursor of cholesterol1. However, the complexity of the insects' vital functions hindered all subsequent attempted transformations into cholesterol1 of sitosterol2, trienol6, and ergosterol4, under injection conditions.

Diversity in steroidogenesis of symbiotic microorganisms from planthoppers.

Phenylalanine and tyrosine give rise to many secondary plant products. Phenylalanine is preferably converted to cinnamic acid, the parent substance of the large group of nonnitrogenous phenylpropanoids (Progr. Bot. 40, 126 ff.; 41, 93ff.; SCHUTTE, 1981). Tyrosine and dopa lead preferably to the corresponding alkaloids. The usual pathway to the alkaloids starts with dopamine (I), the decarboxylation product of dopa, which can give the simple phenethylamines like mescaline (II) (PAUL, 1973; SMITH, 1977; BASMADJIAN et al., 1978) or which can react according to a Mannich reaction with carbonyl compounds to give tetrahydroisoquinolines (cf. LIEBISCH, 1969). Most important is the reaction of dopamine derivatives with phenylpyruvic acid derivatives yielding benzyltetrahydroisoquinolines and the different derived compounds. The principles of this pathway were established in the 1960’s (cf. SCHUTTE, 1969; Herbert, 1979; FODOR, 1980). Here some recent results in this field should be discussed.

Secondary Plant Substances

The hydride shifts accompanying 2,3-epoxysqualene cyclisation to lanosterol in yeast and to β-amyrin in peas have been checked using 2,3-epoxy[11,14-3H2]squalene. The results support the Ruzicka–Eschenmoser hypothesis and not a plausible alternative which was considered. The synthesis of 2,3-epoxy[11,14-3H2]squalene by two routes is described.

J. J. Wright

Papers

Biosynthesis of terpenes and steroids. Part IV. Specific hydride shifts in the biosynthesis of lanosterol and β-amyrin

Biosynth. von terpenen und steroiden 4. mitt. spezifische hydridverschiebungen bei der biosynth. von lanosterin und beta‐amyrin