Sterol

About: Sterol is a research topic. Over the lifetime, 8117 publications have been published within this topic receiving 309926 citations. The topic is also known as: sterols & sterol lipids.

C2'-OH of amphotericin B plays an important role in binding the primary sterol of human cells but not yeast cells.

Abstract: Amphotericin B (AmB) is a clinically vital antimycotic but is limited by its severe toxicity. Binding ergosterol, independent of channel formation, is the primary mechanism by which AmB kills yeast, and binding cholesterol may primarily account for toxicity to human cells. The leading structural model predicts that the C2' hydroxyl group on the mycosamine appendage is critical for binding both sterols. To test this, the C2'-OH was synthetically deleted, and the sterol binding capacity of the resulting derivative, C2'deOAmB, was directly characterized via isothermal titration calorimetry. Surprisingly, C2'deOAmB binds ergosterol and, within the limits of detection of this experiment, does not bind cholesterol. Moreover, C2'deOAmB is nearly equipotent to AmB against yeast but, within the limits of detection of our assays, is nontoxic to human cells in vitro. Thus, the leading structural model for AmB/sterol binding interactions is incorrect, and C2'deOAmB is an exceptionally promising new antifungal agent.

Tellurium blocks cholesterol synthesis by inhibiting squalene metabolism: preferential vulnerability to this metabolic block leads to peripheral nervous system demyelination.

Abstract: Inclusion of 1.1% elemental tellurium in the diet of postweanling rats produces a peripheral neuropathy due to a highly synchronous primary demyelination of sciatic nerve; this demyelination is followed closely by remyelination. Sciatic nerves from animals fed tellurium for various times were removed and incubated ex vivo for 1 h with [14C]acetate, and radioactivity incorporated into individual lipid classes was determined. In nerves from rats exposed to tellurium, there was a profound and selective block in the conversion of radioactive acetate to cholesterol. Another radioactive precursor, [3H]water, gave similar results. We suggest that tellurium feeding inhibits squalene epoxidase activity and that the consequent lack of cholesterol destabilizes myelin, thereby causing destruction of the larger internodes. Ex vivo incubation experiments were also carried out with liver slices. As with nerve, tellurium feeding caused accumulation in squalene of label from radioactive acetate, whereas labeling of cholesterol was greatly inhibited. Unexpectedly, however, incorporation of label from [3H]water into both squalene and cholesterol was increased. Relevant is the demonstration that liver was the primary site of bulk accumulation of squalene, which accounted for 10% of liver dry weight at 5 days. Thus, accumulation of squalene (and other mechanisms, possibly including up-regulation of cholesterol biosynthetic pathways) drives squalene epoxidase activity at normal levels in liver even in the presence of inhibitors of this enzyme. This is reflected by continuing incorporation of [3H]water into cholesterol; incorporation of this precursor takes place at many of the postsqualene biosynthetic steps for sterol formation. [14C]Acetate entering the sterol pathway before squalene in liver is greatly diluted in specific activity when it reaches the large squalene pool, and thus increased squalene epoxidase activity does not transfer significant 14C label to sterols. In contrast to the situation with liver, synthesis of sterols is markedly depressed in sciatic nerve, and squalene does not accumulate to high levels.