Showing papers on "Mevalonic acid published in 1972"
TL;DR: The total biosynthesis of ubiquinone-9 from p-hydroxy[U-14C]benzoate has been demonstrated in mitochondria isolated from rat liver slices preincubated with mevalonic acid and partial reactions were demonstrated, suggesting that the inner membrane of liver mitochondria is capable of the hydroxylation and methylation of aromatic precursors of ubiqu inone.
56 citations
TL;DR: The results suggest that the correlation of retention of the pro-4S hydrogen atom of mevalonate with formation of a cis-substituted double bond, such as has been found in certain higher terpenoids, does not apply to the biosynthesis of monoterpenes.
Abstract: 1. 3R-[2-(14)C]Mevalonate was incorporated into geranyl and neryl beta-d-glucosides in petals of Rosa dilecta in up to 10.6% yield, and the terpenoid part was specifically and equivalently labelled in the moieties derived from isopentenyl pyrophosphate and 3,3-dimethylallyl pyrophosphate. A similar labelling pattern, with incorporations of 0.06-0.1% was found for geraniol or nerol formed in leaves of Pelargonium graveolens The former results provide the best available evidence for the mevalonoid route to regular monoterpenes in higher plants. 2. Incorporation studies with 3RS-[2-(14)C,(4R)-4-(3)H(1)]-mevalonate and its (4S)-isomer showed that the pro-4R hydrogen atom of the precursor was retained and the pro-4S hydrogen atom was eliminated in both alcohols and both glucosides. These results suggest that the correlation of retention of the pro-4S hydrogen atom of mevalonate with formation of a cis-substituted double bond, such as has been found in certain higher terpenoids, does not apply to the biosynthesis of monoterpenes. It is proposed that either nerol is derived from isomerization of geraniol or the two alcohols are directly formed by different prenyltransferases. Possible mechanisms for these processes are discussed. 3. The experiments with [(14)C,(3)H]mevalonate also show that in these higher plants, as has been previously found in animal tissue and yeast, the pro-4S hydrogen atom of mevalonate was lost in the conversion of isopentenyl pyrophosphate into 3,3-dimethylallyl pyrophosphate.
48 citations
TL;DR: Trichothecolone biosynthesized in the presence of doubly labeled mevalonate was degraded to show that the carbon atom at position 8 originated from C(2) of mevalonic acid.
44 citations
TL;DR: The results showed that the doubly unsaturated δ-lactone ring of the bufadieno-lides is directly derived from the cholesterol side chain without the compound's prior conversion into pregnenolone.
42 citations
TL;DR: Mevalonate kinase preparations from Hevea brasiliensis, Cucumis melo, Phaseolus vulgaris and Saccharomyces cerevisiae have been found to be inhibited by geranyl, farnesyl, geranylgeranyl and phytyl pyrophosphates.
42 citations
TL;DR: Great inhibition of liver cholesterogenesis was evident with HMG administration to rats fed cholesterol in the diet than with rats fed only cholesterol, indicating an additive inhibitory effect of HMG.
39 citations
TL;DR: The finding that the prenyltransferase may be the rate-limiting enzyme in squalene synthesis from mevalonate is discussed in relation to regulation of isoprenoid synthesis during pea-seed germination.
Abstract: The activities of individual enzymes of the isoprenoid pathway from mevalonate kinase to squalene synthetase in homogenates of seeds germinated up to 32h were assayed. Changes in the activity of each enzyme were observed and compared with the activity at the 2h germination stage. Activities of alkaline phosphatase and fructose 1,6-diphosphate aldolase were similarly measured to provide a reference for changes in the general metabolic activity of seeds during imbibition of water. Water uptake reached a plateau after 12h. The reference enzymes almost doubled in activity between 2 and 8h and thereafter their activities steadily declined. All of the enzymes of the isoprenoid pathway increased in activity between 2 and 6h and, thereafter, with the exception of the prenyltransferase, their activities remained relatively constant. With the prenyltransferase activity the initial increase was followed by a short plateau between 6 and 9h and then a second increase to a maximum between 14 and 16h. After 16h the activity declined. The relative activities of the isoprenoid enzymes at 16h of germination were mevalonate kinase>phosphomevalonate kinase>pyrophosphomevalonate decarboxylase approximately isopentenyl pyrophosphate isomerase>squalene synthetase>isopentenyl pyrophosphate/dimethylallyl pyrophosphate prenyltransferase. The finding that the prenyltransferase may be the rate-limiting enzyme in squalene synthesis from mevalonate is discussed in relation to regulation of isoprenoid synthesis during pea-seed germination.
32 citations
TL;DR: Alternative mechanisms are proposed for the stereospecific elimination of the 4-pro-S proton of mevalonic acid in the biosynthesis of both cis and trans prenyl pyrophosphates.
32 citations
TL;DR: Bacitracin is an inhibitor of the biosynthesis of squalene and sterols from mevalonic acid, C(5)-isopentenyl pyrophosphate, or C(15)-farnesyl pyphosphate catalyzed by preparations from rat liver.
Abstract: Bacitracin is an inhibitor of the biosynthesis of squalene and sterols from mevalonic acid, C5-isopentenyl pyrophosphate, or C15-farnesyl pyrophosphate catalyzed by preparations from rat liver. The antibiotic is active at extremely low ratios of antibiotic to substrate. The mechanism of inhibition appears to be the formation of a complex between bacitracin, divalent cation, and C15-farnesyl pyrophosphate and other isoprenyl pyrophosphates. It is similar to the formation of the complex with C55-isopropenyl pyrophosphate in microbial systems. The toxicity of bacitracin for animal cells could be due in part to the formation of these complexes.
29 citations
TL;DR: It was concluded that during the reduction of 3-hydroxy-3-methylglutaryl-CoA to mevalonic acid two hydrogen atoms from the 4A (4R) position of NADPH are transferred directly to meValonic acid.
Abstract: 3-Hydroxy-3-methyl-[3-14C]glutaryl-CoA was reduced to mevalonic acid in the presence of either [4A-3H]- or [4B-3H]NADPH and rat liver 3-hydroxy-3-methylglutaryl-CoA reductase. The resulting doubly labelled mevalonic acid incorporated tritium exclusively from the 4A (4R) position of NADPH. The distribution of tritium at C-5 of the mevalonic acid was determined by a biological degradation. It was concluded that during the reduction of 3-hydroxy-3-methylglutaryl-CoA to mevalonic acid two hydrogen atoms from the 4A (4R) position of NADPH are transferred directly to mevalonic acid.
25 citations
TL;DR: The stereochemical relationship between the added and abstracted hydrogen in the prototropic isomerization mediated by this enzyme is established and the chiral methyl groups formed on the enzyme isopentenyl pyrophosphate isomerase are established.
Abstract: Mevalonic acid stereospecifically labelled with tritium in the 2-position was incubated, in a deuterium oxide medium containing adenosine triphosphate, with a soluble enzyme preparation from pig liver; and so converted into farnesyl pyrophosphate. This was hydrolysed enzymically to farnesol which was oxidized, by ozone followed by sodium hypoiodite, to acetic acid originating from the terminal isopropylidene group of farnesol. The tritium in this acetic acid was found, on analysis by a recently developed enzymic method, to be present largely in chiral methyl groups the chirality of which was R or S according to the chirality at C-2 of the parent mevalonic acid. It is deduced that these chiral methyl groups were formed on the enzyme isopentenyl pyrophosphate isomerase, by addition of a deuteron from the medium to the 3 re, 4 re face of the double bond in isopentenyl pyrophosphate. The stereochemical relationship between the added and abstracted hydrogen in the prototropic isomerization mediated by this enzyme is thereby established. A preliminary communication of these results has been made (Clifford, Cornforth, Mallaby & Phillips 1971).
TL;DR: In this article, a study was made of the methyl sterols involved in sterol biosynthesis in developing rat brain and the determination of the endogenous sterols present in 15-day-old rat brain was conducted to establish which of these sterols could be labeled by a minced tissue preparation in the presence of [2-14C]mevalonic acid.
TL;DR: It is shown that significantly more endogenously generated NADPH is available for reduction of corticosterone in liver homogenates from C57BL/10 male mice than in those from the DBA/2 strain, which mainly produces lanosterol and other precursors of cholesterol which require NADPH for their further metabolism.
01 Jan 1972
TL;DR: Many of the questions about the role played by abscisic acid (ABA) in plants are at present unanswerable because we do not know enough of the metabolism of the hormone or the factors which influence its transport as mentioned in this paper.
Abstract: Many of the questions we have been asking about the role played by abscisic acid (ABA) in plants are at present unanswerable because we do not know enough of the metabolism of the hormone or the factors which influence its transport. As usual, the more we have found out the less sure we are of earlier results.
TL;DR: Cell-free extracts and acetone powder preparations from Agave americana phosphorylated mevalonic acid to phosphomevalonic Acid (MVAP) and pyrophosphorylation of the compounds formed and Flowers of the Agave show more activity than leaves and scape.
TL;DR: The presence of tritium at C-25 is consistent with the involvement of a 24-ethylidene sterol in the C-24 alkylation mechanism in this organism.
TL;DR: It is concluded that this insect is capable of isoprenoid biosynthesis at least to this point, and that the block in the cholesterol biosynthetic pathway lies beyond.
TL;DR: In all experiments most of the radioactivity of the liver was transformed to cholesterol and the conversion of squalene to cholesterol proceeded more slowly in the kidneys and 30 min after the administration of the mevalonate substantial amounts of radioactivity was recovered as labelledsqualene and lanosterol.
Abstract: DL-mevalonate-2-14C was administered parenterally to 2 rabbits and 5 groups of mice. In the rabbits the amount of labelled material recovered in the non-saponifiable lipids of the kidneys exceeded that of the liver. Most of the renal radioactivity was found in the squalene, lanosterol and methostenol fractions whereas the major part of the labelled material in the liver was present as radioactive cholesterol. The distribution of radioactivity within the kidney and the liver in the mice varied with the size of the administered dose. The smaller the dose, the larger the proportion of label recovered in the kidneys. In all experiments most of the radioactivity of the liver was transformed to cholesterol. The conversion of squalene to cholesterol proceeded more slowly in the kidneys and 30 min after the administration of the mevalonate substantial amounts of radioactivity was recovered as labelled squalene and lanosterol. The importance of circulating mevalonate as substrate in the cholesterol synthesis of the kidney will be discussed.
TL;DR: Incorporation of [2-14C-(4R)-4-3H1]mevalonic acid into sitosterol in Larix decidua demonstrates that during alkylation, the C-24 hydrogen of the Δ24 precursor is eliminated.
Abstract: Incorporation of [2-14C-(4R)-4-3H1]mevalonic acid into sitosterol in Larix decidua demonstrates that during alkylation, the C-24 hydrogen of the Δ24 precursor is eliminated.
TL;DR: The results strongly suggest that the rate of biosynthesis of mevalonate, the precursor of the poly-isoprenoid side chain, is the probable limiting factor in the biogenesis of ubiquinone in the rat.
Abstract: Mevalonate, added in the incubation medium, increases by nearly two-fold the biosynthesis of ubiquinone in liver slices as evidenced by enhanced incorporation of radioactivity from labeled precursors of the benzoquinone moiety such as [1-14C]benzoate and [Me-14C]methionine Other intermediates of isoprenoid biosynthesis such as mevalonic acid 5-pyrophosphate and isopentenyl pyrophosphate show a qualitatively similar effect on labeling of ubiquinone The stimulation due to mevalonate is even more marked under conditions in which its endogenous synthesis and/or utilisation is known to be impaired such as in liver slices from fasted or cholesterol-fed rats and in liver slices from normal animals incubated in the presence of vanadium ions These results strongly suggest that the rate of biosynthesis of mevalonate, the precursor of the poly-isoprenoid side chain, is the probable limiting factor in the biogenesis of ubiquinone in the rat
TL;DR: The labelling pattern in linalools biosynthesized from [2-14C] mevalonic acid in Cinnamomum Camphora Sieb.
Abstract: The labelling pattern in linalool biosynthesized from [2-14C] mevalonic acid in Cinnamomum Camphora Sieb. var. linalooliferum Fujita was found to be consistent with the predicted biosynthetic pathway involving the condensation of isopentenyl pyrophosphate with 3,3-dimethylallyl pyrophosphate. The radioactivities at C-4 and C-8 (and/or C-10) were about equal, in contrast to the asymmetric pattern of labelling observed for bicyclic monoterpenes, which contained a tracer predominantly in one position of the skeleton derived from isopentenyl pyrophosphate. The efficiency of the incorporation of the tracer into linalool was almost independent of the season of the examination, although a slight increase was observed in the season of the active growth of the plant.
TL;DR: It appears that the increased incorporation of mevalonate into the lipids of the nephrotic animals reflected a hyperactive lipid synthesis in extrarenal tissues, rather than a deranged metabolism of circulating mevalanate due to the renal lesion.
Abstract: DL-Mevalonate-2–14C was injected intravenously to control and nephrotic rats. The predominant part of the radioactivity recovered after 90 min as nonsaponifiable lipids in the control rats was found in the kidneys. In agreement with previous studies, most of the label in the nonsaponifiable lipid fraction of the blood and liver was localized to material tentatively identified as C27 sterols (cholesterol), whereas more than 50% of such radioactivity in the kidneys appeared to be attached to labelled squalene and lanosterol. The total recovery of labelled nonsaponifiable lipids was higher in the nephrotic than in the control rats. The difference was mainly due to a 3–4-fold elevation of such material in the liver, whereas the recovery in the kidneys was essentially the same in both groups of animals. The distribution of radioactivity among squalene, lanosterol and C27 sterols was essentially normal in all tissues of the nephrotic rats studied. It appears that the increased incorporation of mevalonate into the lipids of the nephrotic animals reflected a hyperactive lipid synthesis in extrarenal tissues, rather than a deranged metabolism of circulating mevalonate due to the renal lesion.
TL;DR: Tutin from (4R)-[4-3H1]mevalonic acid retains one tritium atom at C-4, thus excluding a double 1–2 hydride shift during the cyclization steps of its biosynthesis.
Abstract: Tutin from (4R)-[4-3H1]mevalonic acid retains one tritium atom at C-4, thus excluding a double 1–2 hydride shift during the cyclization steps of its biosynthesis.
TL;DR: A tracer pattern in (+)-pulegone [p-menth-4(8)-en-3-one] indicated extensive degradation of the additive and probable incorporation as acetate units as mentioned in this paper.
Abstract: Feeding of 3,3-dimethyl[1-14C]acrylic acid to Mentha pulegium L. led to a tracer pattern in (+)-pulegone [p-menth-4(8)-en-3-one] that indicated extensive degradation of the additive and probable incorporation as acetate units. A previous report of intact incorporation of the acid could not be substantiated.[2-14C] Mevalonic acid was incorporated into (+)-pulegone to give asymmetric labelling whereby almost all the tracer was associated with the isopentenyl pyrophosphate portion. The pattern also showed that if (as is believed on the basis of time-incorporation studies) terpinolene [p-mentha-1,4(8)-diene] was a precursor of pulegone, oxidation at the two positions α to the exocyclic double bond occurred at comparable rates.
TL;DR: Incorporation of mevalonic acid and cholesterol into ecdysone and ecdysterone and conversion of ecDysone into ecdystersone in the plant, Sesuvium portulacastrum L., have been demonstrated.
Abstract: Incorporation of mevalonic acid and cholesterol into ecdysone and ecdysterone and conversion of ecdysone into ecdysterone in the plant, Sesuvium portulacastrum L., have been demonstrated.
TL;DR: The distribution of deuterium in squalene and β-amyrin biosynthesized from [6-D3]-mevalonic acid in Pisum sativum has been analyzed by NMR spectroscopy as mentioned in this paper.
Abstract: The distribution of deuterium in squalene and β-amyrin biosynthesized from [6-D3]-mevalonic acid in Pisum sativum has been analyzed by NMR spectroscopy. It was thus proved that the cis-terminal methyls of squalene and the 4β-methyl group of β-amyrin are stereospecifically derived from the 3-methyl group of mevalonic acid.