Inhibitory properties of 1,4-dideoxy-1,4-imino-d-arabinitol (DAB) derivatives acting on glycogen metabolising enzymes

Abstract

Glycogen synthase (GS) and glycogen phosphorylase (GP) are the key enzymes that control, respectively, the synthesis and degradation of glycogen, a multi-branched glucose polymer that serves as a form of energy storage in bacteria, fungi and animals. An abnormal glycogen metabolism is associated with several human diseases. Thus, GS and GP constitute adequate pharmacological targets to modulate cellular glycogen levels by means of their selective inhibition. The compound 1,4-dideoxy-1,4-imino-D-arabi-nitol (DAB) is a known potent inhibitor of GP. We studied the inhibitory effect of DAB, its enantiomer LAB, and 29 DAB derivatives on the activity of rat muscle glycogen phosphorylase (RMGP) and E. coli glycogen synthase (EcGS). The isoform 4 of sucrose synthase (SuSy4) from Solanum tuberosum L. was also included in the study for comparative purposes. Although these three enzymes possess highly conserved catalytic site architectures, the DAB derivatives analysed showed extremely diverse inhibitory potential. Subtle changes in the positions of crucial residues in their active sites are sufficient to discriminate among the structural differences of the tested inhibitors. For the two Leloir-type enzymes, EcGS and SuSy4, which use sugar nucleotides as donors, the inhibitory potency of the compounds analysed was synergistically enhanced by more than three orders of magnitude in the presence of ADP and UDP, respectively. Our results are consistent with a model in which these compounds bind to the subsite in the active centre of the enzymes that is normally occupied by the glucosyl residue which is transferred between donor and acceptor substrates. The ability to selectively inhibit the catalytic activity of the key enzymes of the glycogen metabolism may represent a new approach for the treatment of disorders of the glycogen metabolism.

Physiological adaptations to sugar‐mimic alkaloids: Insights from Bombyx mori for long‐term adaption and short‐term response

“…In addition, several pathways related to digestive systems were also enriched (Figure 3). D‐AB1 had negative influence on sugar metabolism of insects (Asano et al., 2001; Diaz‐Lobo et al., 2016). As expected, the DEGs in glycosphingolipid biosynthesis pathways and other digestive pathways were mostly downregulated.…”

“…In addition, several pathways related to digestive systems were also enriched (Figure 3). D-AB1 had negative influence on sugar metabolism of insects (Asano et al, 2001;Diaz-Lobo et al, 2016).…”

“…However, the concentration of D‐AB1 varies remarkably between mulberry populations and cultivars. D‐AB1 is a potent inhibitor of glycogen phosphorylase and synthase activity, and it appears to exert adverse effects on insects by interfering with sugar metabolism in ways that are similar to their antidiabetic activities (Asano et al., 2001; Diaz‐Lobo et al., 2016). Thus, mulberry‐specialist insects need to have the physiological capacity to deal with changing levels of sugar‐mimic alkaloids.…”

Noradrenaline‐induced l‐lactate production requires d‐glucose entry and transit through the glycogen shunt in single‐cultured rat astrocytes

“…DAB is an allosteric inhibitor, promoting conversion of inactive glycogen phosphorylase b into active glycogen phosphorylase a (GPa) (Latsis et al., 2002). DAB binds a free GPa or GPa‐Pi complex due to its glycomimetic structure (Díaz‐Lobo et al., 2016). This in turn inhibits synthase phosphatase, resulting in a reduced activity of glycogen synthase (GS) (Walls et al., 2008).…”

Glucose-based spiro-oxathiazoles as in vivo anti-hyperglycemic agents through glycogen phosphorylase inhibition

“…A broad variety of synthetic compounds and natural products have been tested as inhibitors of glycogen phosphorylase (GP) [6][7][8][9][10][11][12] mainly with the most easily available rabbit muscle GPb (RMGPb). 13 Many of these compounds' complexes with the GP enzyme were also studied by X-ray crystallography.…”