Plant Glycosides and Glycosidases: A Treasure-Trove for Therapeutics

Abstract

Plants contain numerous glycoconjugates that are metabolized by specific glucosyltransferases and hydrolyzed by specific glycosidases, some also catalyzing synthetic transglycosylation reactions. The documented value of plant-derived glycoconjugates to beneficially modulate metabolism is first addressed. Next, focus is given to glycosidases, the central theme of the review. The therapeutic value of plant glycosidases is discussed as well as the present production in plant platforms of therapeutic human glycosidases used in enzyme replacement therapies. The increasing knowledge on glycosidases, including structure and catalytic mechanism, is described. The novel insights have allowed the design of functionalized highly specific suicide inhibitors of glycosidases. These so-called activity-based probes allow unprecedented visualization of glycosidases cross-species. Here, special attention is paid on the use of such probes in plant science that promote the discovery of novel enzymes and the identification of potential therapeutic inhibitors and chaperones.

Keywords: carbohydrate processing enzymes; enzyme replacement therapy (ERT); glycosidase activity-based probes; glycosidases; glycosphingolipids; glycosylation; plant glycosides; plant production platforms.

FIGURE 1

Glycosylated plant metabolites beneficial for humans. Flavonoids and some of their glycoside metabolites: flavonols (A), flavones (B), isoflavones (C), flavanones (D), flavanols (E), and anthocyanidins (F). Chemical structures of cardiac glycosides (G). Bufalin is an animal-derived cardiac glycoside.

FIGURE 2

Different classes of plant lipids and their localization in the plant cell. (A) Chemical structures of plant glycosylated lipids: monogalactosyldiacylglycerol (MGDG) and digalactosyldiacylglycerol (DGDG). (B) Chemical structures of plant (glycosyl)sphingolipids: long-chain base (LCB) 4,8-sphingadienine, ceramide (Cer), glucosylceramide (GlcCer), glucosylinositol phosphoryl ceramides (GIPC) and oligoglycosylceramide. (C) Chemical structures of plant sterols (green) versus the animal counterparts (blue). Plant cell image illustrating the localization of lipid classes: (A) stands for MGDG and DGDG, (B) for plant (glycosyl)sphingolipids, and (C) for plant sterols.

FIGURE 3

Activity based probes mechanism and use in plant science. (A) Mechanism of aziridine and epoxide activity-based probes. (B) Structures of ABPs used in plant science. (C) Summary of published ABPs used in plant research. Presented are key publications describing specific applications in plant species.

FIGURE 4

Plant and human N-glycosylation pathways: importance in production of pharmaceuticals. (A) N-linked glycosylation pathway of proteins produced in plants and humans. (B) The lectin mediated uptake of recombinant enzymes from cells for the treatment of LSDs.

FIGURE 5

Principle of activity-based protein profiling for target identification and competitive activity-based protein profiling for the screening of glycosidase inhibitors. The competition of ABP labeling of a glycosidase by agents interacting with its pocket (inhibitors, substrates) can be conveniently and sensitively assessed. there is no need for a pure enzyme, when visualizing labeled glycosidase using SDS-PAGE and fluorescence scanning.