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At least 19 recordsLinked to original sources
PubMed1976

[Possible role of acetyl-CoA-carboxylase in biosynthesis of mevalonic acid and sterols in rat liver].

Effect of citrate on acetyl-CoA incorporation into mevalonic acid, sterols and fatty acids after preliminary incubation of rat liver extracts under conditions optimal for acetyl-CoA carboxylase activation, was studied. 30 min preincubation with the citrate at 37 degrees C results in a 2--3-fold stimulation of the mevalonic acid biosynthesis from acetyl-CoA in the microsomal and soluble (140 000 g) fraction, and in that of sterols precipitated by digitonin or isolated by TLC in the mitochondria--free fraction. 2-14C-malonyl-CoA incorporation into the mevalonic acid and sterols and biosynthesis of sterols from 2-14C-mevalonic acid were not stimulated under those conditions. A correlation was shown to exist between the activity of acetyl-CoA carboxylase and the rate of acetyl-CoA incorporation into mevalonate and sterols; the activity of beta-hydroxy-beta-methylglutaryl-CoA reductase, limiting the rate of the sterol biosynthesis, was not changed. The stimulating effect of citrate was found to depend on the concentration of acetyl-CoA and NADPH in the medium. The data obtained suggest that the mevalonic acid biosynthesis in rat liver may occur in the presence of acetyl-CoA carboxylase through the formation of malonyl-CoA.

Acetyl-CoA Carboxylase↗
PubMed1977

Measurement of daily cholesterol synthesis rates in man by assay of the fractional conversion of mevalonic acid to cholesterol.

A significant correlation has been found in man between total daily cholesterol synthesis rates as determined by sterol balance measurements and the fraction of intravenously administered R-[5-14C]mevalonic acid converted to cholesterol. In 30 studies it was found that the mean daily cholesterol synthesis rates estimated by sterol balance measurements ranged from 395 to 3047 mg/day, whereas the fractional conversion of mevalonate to cholesterol varied from 0.28 to 0.99. The two parameters correlated with a coefficient of 0.87, P less than 0.001. This method for estimating cholesterol synthesis rates requires low doses of radioisotopic materials (25 muCi of [14C]mevalonate and 5 muCi of [3H]cholesterol) and less than 1 hr of the patient's time; it can be repeated at intervals of 3 weeks and reflects cholesterol synthesis over a short period of time.

Adult↗
PubMed1979

Isolation of 4 alpha-methyl-5 alpha-ergosta-8,24(28)-dien-3 beta-ol from ester fractions of nutritionally deprived Neurospora crassa.

A method of isolating pure fractions of 4 alpha-methyl-5 alpha-ergosta-8,24(28)-dien-38-ol for sterol intermediate studies is described. Starvation cultures of Neurospora crassa readily incorporate exogenous mevalonic acid into the sterol ester fraction. Isolation involves a simple solvent extraction and two chromatograms. Only the ester fraction yielded the required purity. Radioactive 4 alpha-methyl-5 alpha-ergosta-8,24(28)-dien-3 beta-ol is readily produced from DL-[2-14C] mevalonic acid.

Cholestadienols↗
PubMed1976

Kinetic analysis of the individual reductive steps catalyzed by beta-hydroxy-beta-methylglutaryl-coenzyme A reductase obtained from yeast.

The mechanism of action of yeast beta-hydroxy-beta-methylglutaryl-coenzyme A reductase has been investigated through kinetic studies on the oxidation of mevaldate by nicotinamide adeninine dinucleotide phosphate (NADP) in the presence of coenzyme A (CoA) and on the reduction of mevaldate by reduced NADP (NADPH) in the absence of presence of CoA or acetyl-CoA. NADP and mevalonate were also used as product inhibitors of the reduction of mevaldate. In the reduction of mevaldate to mevalonate, coenzyme A and acetyl-CoA decreased the Km for mevaldate 30- and 3-fold, respectively. Both compounds increased the Vmax 1.5-fold. These results suggest that CoA is an allosteric activator for the second reductive step and that it acts by enhancing the binding of mevaldate. The intersecting patterns obtained from initial velocities and the patterns produced by product inhibitions suggest the following features of the mechanism. The binding of substrates and release of products proceeds sequentially in both reductive steps, and is ordered throughout or random with respect to the binding of the beta-hydroxy-beta-methylglutaryl-coenzymeA and the first NADPH. The binding of NADPH enhances the binding of the beta-hydroxy-beta-methylglutaryl portion of the CoA ester and the binding of free mevaldate, whereas the binding of NADP leads to an increased affinity of the enzyme for the hemithioacetal (of mevaldate and CoA) and for mevalonate. Thus, the replacement of NADP by NADPH after the first reductive step promotes the conversion of the hemithioacetal to the free carbonyl form, which is then rapidly reduced. The products, CoA and mevalonic acid, of the second reductive step leave the enzyme before the release of the second NADP. This release of the last product is probably the rate-limiting step for the overall process.

Alcohol Oxidoreductases↗
PubMed1979

The biosynthesis of the free sterols and sterol esters of Neurospora crassa.

The composition of the free and esterified sterols in Neurospora crassa was examined as a function of incubation time in starvation medium containing [2-14C]mevalonic acid. The 14C incorporation was monitored in nuclear methylated and 4,14-desmethyl sterol fractions. After 7 h incubation, sterol esterification had increased from an initial 5% in the log phase culture to 48% of the total sterol pool, with a concomitant decrease in free sterols. The relationship of the free and esterified sterol components in ergosterol biosynthesis is discussed.

Esters↗
PubMed1976

The transport of esterified cholesterol in plasma high density lipoproteins of human subjects: a mathematical model.

The pattern of labeling of free and esterified cholesterol in the plasma high-density lipoproteins after an intravenous injection of [3H]-mevalonic acid has been examined in six human subjects with a variety of plasma lipoprotein phenotypes. Attempts have been made to fit these data to theoretical models of high-density lipoprotein esterified cholesterol transport constructed on the basis of previous experimental observation. The first model, which assumed that the high-density lipoprotein esterified cholesterol transport constructed on the basis of previous experimental observation. The first model, which assumed that the high-density lipoprotein esterified cholesterol comprised a single homogeneous pool, was incompatible with the observed data. The second model assumed a two-pool model in which all of the plasma esterified cholesterol was produced in a small, rapidly turning over subfraction of the high-density lipoproteins. From this pool it was assumed that esterified cholesterol was transferred to other lipoprotein fractions, including transfer to a larger and much more slowly turning over subfraction of the high density lipoproteins. The second model was quite compatible with the observed data. Furthermore, the calculated net transport of esterified cholesterol through the fast turning over pool was in a range similar to that reported elsewhere for whole plasma. It has been concluded that the two-pool model not only fits the experimental data, but also accords well with previously documented observations of plasma esterified cholesterol transport.

Adult↗
PubMed1979

The in vivo metabolism of esterified cholesterol in the plasma high-density lipoproteins of rabbits.

The in vivo metabolism of esterified cholesterol in plasma HDL has been studied in rabbits injected with preparations of HDL which had been labeled with 3H in the esterified and free cholesterol moieties. These labeled HDL preparations had been isolated either from the serum of donor rabbits which had been previously injected with 3H-mevalonic acid or from rabbit serum which had been incubated in vitro at 37 degrees with 3H-cholesterol. In terms of subsequent in vivo metabolism, there were no significant differences between the in vivo labeled and in vitro labeled HDL preparations. It was also found that the presence of free 3H-cholesterol in the injected HDL had very little effect on the recipient esterified 3H-cholesterol results. The removal of esterified 3H-cholesterol from the recipient HDL fraction was biphasic, with the initial phase largely reflecting a transfer into the plasma VLDL and LDL fractions rather than a removal from the plasma compartment. In fact, the initial rate of removal from HDL was very much influenced by the distribution of esterified cholesterol mass in the different lipoprotein fractions; the greater the proportion in VLDL and LDL, the more rapid was the initial rate of removal from HDL. A transfer of esterified cholesterol from HDL to VLDL and LDL was estimated to be of the order of 150 to 200 mumol/L of plasma per hour, a value much greater than the reported rate of production of esterified cholesterol in rabbit plasma. The implication that such transfers might therefore have been partially reversible was confirmed in in vitro incubations of labeled HDL and unlabeled rabbit serum.

Animals↗
PubMed1979

Quantification of the hepatic contribution to the catabolism of high density lipoproteins in rats.

Isolated rat livers were perfused for four hours in a recirculating system containing washed rat erythrocytes. Biologically screened radioiodinated rat high density lipoproteins (1.090 < d < 1.21 g/ml) were added to the perfusate with different amounts of whole serum to supply unlabeled rat high density lipoproteins. The protein moiety of the lipoprotein contained more than 95% of the radioiodine. The fraction of apolipoprotein mass degraded during the perfusion was quantified by the linear increment of non-protein-bound radioiodine in the perfusate, corrected for the increment observed during recirculation of the perfusate in the absence of a liver. The small amount of (131)I secreted into bile was added to calculate the fractional catabolic rate. The fractional catabolic rate ranged from 0.22 to 0.63% per hour in 12 experiments and was inversely related to the size of the perfusate pool of high density apolipoprotein. The absolute catabolic rate of high density apolipoprotein (fractional catabolic rate x pool size) in three livers in which the concentration of rat HDL in the perfusate approximated that in intact rats was 69.5 +/- 10.4 micro g hr(-1) (mean +/- SD). The rate of disappearance of cholesteryl esters of rat high density lipoproteins (labeled biologically by injecting donor rats with [5-(3)H]mevalonic acid) from the liver perfusate did not exceed that of the apoprotein component. These rates were compared with catabolic rates for rat high density lipoproteins in intact rats. Fractional catabolic rate in vivo, obtained by multicompartmental analysis of the disappearance curve of (131)I-high density apolipoprotein from blood plasma, was 11.9 +/- 1.3% hr(-1) (mean +/- SD). Total catabolic rate in vivo (fractional catabolic rate x intravascular pool of high density apolipoprotein) was 986 +/- 145 micro g hr(-1) (mean +/- SD). The results suggest that only a small fraction of high density lipoproteins in blood plasma of rats is degraded directly by the liver.-Sigurdsson, G., S-P. Noel, and R. J. Havel. Quantification of the hepatic contribution to the catabolism of high density lipoproteins in rats.

Animals↗
PubMed1977

Effect in vitro of 3-hydroxy-3-methylglutaric acid on the synthesis of mevalonate and its precursors.

Addition of 3-hydroxy-3-methylglutaric acid (free HMG) to supernatant-microsomal preparation decreased the synthesis of acetoacetate, HMG-CoA and mevalonolactone by 12%, 33% and 75%, respectively, from [2-14C] acetate. Free HMG also inhibited the activity of HMG-CoA reductase in the microsomes. It is concluded that HMG, apart from inhibiting the activity of HMG-CoA reductase (the rate limiting enzyme in cholesterogenesis) also interferes with the enzymatic steps involved in the conversion of acetate to HMG-CoA.

Acetates↗
PubMed1977

Control of 3-hydroxy-3-methylglutaryl coenzyme A reductase by endogenously synthesized sterols in vitro and in vivo.

Isolated rat hepatocytes converted mevalonolactone into sterol intermediates and fatty acids 6- to 8-fold faster than mevalonate salt at concentrations less than 6 X 10(-4) M. Incubation of hepatocytes for 3 h normally results in induction of 3-hydroxy-3-methylglutaryl-CoA reductase. This increase in enzyme activity was inhibited by mevalonolactone and by mevalonate salt; at each concentration between 6 X 10(-4) M and 6 X 10(-8) M the lactone was a more effective inhibitor than the salt. The increase in enzyme activity was completely prevented by 6 X 10(-4) M lactone, and at this concentration the cells synthesized from the lactone an amount of sterol per hour which approximated that leavingthe cells in the same period. Administration of mevalonolactone to intact rats resulted in a dose-dependent inhibition of hepatic 3-hydroxy-3-methylglutaryl-CoA reductase activity. At the highest dose (400 mg of (RS)-mevalonolactone/200 g of rat) enzyme activities declined 85% within 45 min and were still suppressed below normals after 28 h. Mevalonolactone treatment resulted in increases in liver cholesterol content and in the cholesterol ester concentration of liver microsomes. The results demonstrate that the activity of hepatic 3-hydroxy-3-methylglutaryl-CoA reductase can be controlled by the rate of endogenous sterol synthesis both in vitro and in vivo.

Alcohol Oxidoreductases↗
PubMed1975

Effect of plasma lipoproteins and lecithin-cholesterol dispersions on the activity of 3-hydroxy-3-methylglutaryl-coenzyme A reductase of isolated rat hepatocytes.

Incubation of rat hepatocytes for 3 h in a medium containing amino acids, salts and albumin resulted in a 2-fold increase in the activity of 3-hydroxy-3-methylglutaryl-CoA reductase. Inclusion of 10% human plasma, rat serum or dialysed rat serum in the medium resulted in an approximate 7-fold increase in reductase activity. These increases were specific since there was little change in the rate of fatty acid synthesis or in the activity of tyrosine aminotransferase. Reductase levels were increased above control values when high density lipoproteins or leithin dispersions were added to the cells. Lecithin dispersions were also shown to increase the rate of efflux of cell cholesterol to the medium. In contrast, reductase levels were reduced when cells were incubated with low density lipoproteins or cholesterol added as an equimolar cholesterol-lecithin dispersion. This inhibition of the reductase by cholesterol dispersions was dependent on the continued de novo protein synthesis. Our data indicate that in normal rat hepatocytes the relative rates of efflux and influx of cholesterol may be critical to the regulation of 3-hydroxy-3-methylglutaryl-CoA reductase activity and cholesterogenesis.

Acetates↗
PubMed2026

Characterisation of metabolic burden in Pseudomonas putida reveals precursor limitation in heterologous lycopene production.

BACKGROUND: The introduction of heterologous pathways into microbial hosts often imposes a metabolic burden on the cell, arising from three major physiological constraint layers: competition for gene expression resources, limited precursor availability and flux distribution, and insufficient energy and redox supply. Although Pseudomonas putida KT2440 is considered a robust and metabolically versatile production host, it remains unclear which of these constraint layers primarily limits heterologous terpenoid production in this organism. Here, lycopene biosynthesis was used as a model system to systematically dissect these three potential sources of metabolic burden. RESULTS: A capacity-monitoring system revealed no clear reduction in transcriptional or translational capacity across the tested strains and cultivation conditions, indicating that general gene expression capacity was not the primary limiting factor. Instead, lycopene production depended strongly on promoter architecture and plasmid backbone, showing that regulatory design shaped pathway performance. Enhancing precursor supply by introducing a heterologous mevalonate (MVA) pathway substantially increased product titres, identifying precursor availability from the native MEP pathway as the dominant bottleneck. This conclusion was independently supported by exogenous mevalonate supplementation, which further increased lycopene accumulation but also revealed saturation at higher concentrations, suggesting that downstream pathway balance or enzyme capacity became limiting once precursor supply was relieved. Under controlled bioreactor conditions, lycopene titres increased from approximately 1&#xa0;mg/L to nearly 25&#xa0;mg/L, indicating that process conditions further modulate production performance, suggesting an additional contribution of process-dependent energy and redox constraints. CONCLUSION: Metabolic burden during heterologous lycopene production in P. putida is governed primarily by precursor availability rather than by limitations in general gene expression capacity. Regulatory properties of the vector system strongly influence pathway performance, while controlled cultivation conditions can further improve production by alleviating additional process-dependent constraints. Together, these findings provide a systematic framework for distinguishing constraint layers and guiding the optimisation of heterologous terpenoid production systems.

Lycopene↗