Molecular basis of glycoalkaloid induced membrane disruption

Abstract

In this study the interaction between the glycoalkaloids alpha-chaconine, alpha-solanine and alpha-tomatine and sterols in model membranes was analysed systematically using techniques like membrane leakage, binding experiments, detergent extraction, electron microscopy, NMR and molecular modelling. The most important properties for sterols to interact with glycoalkaloids turned out to be a planer ring structure and a 3 beta-OH group, whereas for alpha-chaconine the 5-6 double bond and the 10-methyl group were also of importance. The importance of sugar-sugar interactions was illustrated by the high synergistic effect between alpha-chaconine and alpha-solanine, the leakage enhancing effect of glycolipids, and the almost complete loss of activity after deleting one or more mono-saccharides from the glycoalkaloids. The formed complexes which were resistant against detergent extraction existed of glycoalkaloid/sterol in a 1:1 ratio and formed tubular structures (alpha-chaconine) with an inner monolayer of phospholipids, whereas with alpha-tomatine also spherical structures were formed. Based on the results a molecular model for glycoalkaloid induced membrane disruption is presented.

Induction of Highly Curved Structures in Relation to Membrane Permeabilization and Budding by the Triterpenoid Saponins, α- and δ-Hederin

“…It appears that a certain cholesterol density in the liposomes is required to allow ␣-hederin to induce pores. The importance of this threshold for pore formation by other saponins agrees with observations reported by others (9,10,75,76). On cells, THP-1 macrophages depleted in cholesterol were protected against cytotoxicity induced by ␣-hederin.…”

“…buds or small unilamellar vesicles (46 -48, 67), are the most likely. The hexagonal pattern observed at the highest temperature and ␣-hederin concentration could probably be associated with tubular structures as it has been suggested for glycoalkaloids (10).…”

“…In particular, the interaction with cholesterol has been suggested to be involved in the membrane permeabilization by monodesmosidic saponins with a sugar moiety at C3 (9,10).…”

The anticancer activity of alpha-tomatine against mammary adenocarcinoma in mice

“…This synergism may also be the result of P-gp (permeability glycoprotein) efflux transporter blockade, which was detected previously for tomatidine, the aglycon of ΤΟΜ 31 . The impact on cell membrane structures would be even more important for the overall action of ΤΟΜ because it interacts strongly with cholesterol and may cause cell membrane disruption and intracellular stress [32][33][34] . Whether TOM can also induce apoptosis in solid tumours such as mammary adenocarcinoma in the manner described by Chao et al 16 will need to be clarified by further investigation.…”

In Vitro Sensitivity of Botrytis Cinérea to Resinous Exudates of Heliotropium Filifoliumand Geranyl Derivatives Compounds

“…Some flavonoids, 12 diterpenoids, 13,14 sequiterpenoids, 15 monoterpenoids, 16 stilbenes, 17,18 steroidal glycoalkaloid [19][20][21] and triterpenoids 22 have effect against this fungus (inhibition mycelia growth, cytological changes, toxic action and protection cucumber tissue, etc).…”