OleD Loki as a Catalyst for Hydroxamate Glycosylation

Area of Science:

• Biochemistry
• Enzymology
• Medicinal Chemistry

Background:

• Histone deacetylase inhibitors (HDACis) are a class of drugs with therapeutic potential.
• Glycosylation is a key post-translational modification with implications in drug development.
• The enzyme OleD Loki is a glycosyltransferase (GT) with known substrate flexibility.

Purpose of the Study:

• To investigate the ability of the glycosyltransferase (GT) OleD Loki to glycosylate various histone deacetylase inhibitors (HDACis).
• To evaluate the biological activity and properties of the resulting glycosyl esters.
• To explore the mechanistic basis of GT-substrate interactions using computational modeling.

Main Methods:

• Enzymatic reactions using OleD Loki and >15 different HDACis.
• Assays for cancer cell line cytotoxicity.
• Chemical and enzymatic stability assessments.
• Axolotl embryo tail regeneration assays.
• Computational substrate docking models.

Main Results:

• OleD Loki successfully converted >15 HDACis into their corresponding hydroxamate glycosyl esters.
• Representative glycosyl esters demonstrated cytotoxicity against cancer cell lines.
• The glycosyl esters exhibited varying degrees of chemical and enzymatic stability.
• Axolotl embryo tail regeneration assays provided insights into potential in vivo effects.
• Docking models accurately predicted enzyme-catalyzed turnover for some substrates.
• Certain HDACis were predicted to form unproductive complexes with GTs.

Conclusions:

• The permissive glycosyltransferase OleD Loki can be utilized to synthesize novel glycosyl ester derivatives of HDACis.
• These glycosyl esters represent a new class of compounds with potential anticancer and regenerative applications.
• Understanding GT-substrate interactions is crucial for optimizing enzymatic synthesis and predicting enzyme activity.
• Further research is warranted to fully elucidate the therapeutic potential of these glycosylated HDACis.