Abstract
Capsaicinoids are phenolic compounds that have health benefits. However, the pungency and poor water solubility of these compounds limit their exploitation. Glycosylation is a powerful method to improve water solubility and reduce pungency while preserving bioactivity. PaGT3, a uridine diphosphate glycosyltransferase (UGT) from Phytolacca americana, is known for its ability to glycosylate capsaicinoids and other phenolic compounds. While structural information on several UGTs is available, structures of UGTs that can glycosylate a range of phenolic compounds are rare. To fill this gap, crystal structures of PaGT3 with a sugar-donor analogue (UDP-2-fluoroglucose) and the acceptors capsaicin and kaempferol were determined. PaGT3 adopts a GT-B-fold structure that is highly conserved among UGTs. However, the acceptor-binding pocket in PaGT3 is hydrophobic and large, and is surrounded by longer loops. The larger acceptor-binding pocket in PaGT3 allows the enzyme to bind a range of compounds, while the flexibility of the longer loops possibly plays a role in accommodating the acceptors in the binding pocket according to their shape and size. This structural information provides insights into the acceptor-binding mechanism in UGTs that bind multiple substrates.
Highlights
Capsaicinoids are compounds with a pungent taste that are produced by plants belonging to the genus Capsicum
Capsaicin shows a cardioprotective effect through the activation of transient receptor potential vanilloid 1 (TRPV1) and inhibition of platelet aggregation (Mittelstadt et al, 2012; Sharma et al, 2013)
uridine diphosphate glycosyltransferase (UGT) share a conserved three-dimensional structure, known as a GT-B fold, consisting of two Rossmann-fold domains. These enzymes are characterized by the presence of a consensus plant secondary product glycosyltransferase (PSPG) motif, which contains most of the residues involved in UDP-sugar donor binding (Offen et al, 2006; Lim & Bowles, 2004)
Summary
UGTs share a conserved three-dimensional structure, known as a GT-B fold, consisting of two Rossmann-fold domains These enzymes are characterized by the presence of a consensus plant secondary product glycosyltransferase (PSPG) motif, which contains most of the residues involved in UDP-sugar donor binding (Offen et al, 2006; Lim & Bowles, 2004). Crystal structures of the promiscuous UGTs PaGT3 (Maharjan, Fukuda, Nakayama et al, 2020) and Bs-YjiC (Dai et al, 2021) are available, these structures do not contain acceptors These structures do not provide sufficient information to understand the acceptor-recognition mechanisms in such promiscuous UGTs. capsaicin glycosides have been enzymatically synthesized using different cultured plant cells (Shimoda et al, 2007; Katsuragi et al, 2010, 2011). The structure of PaGT3 with capsaicin provides a mechanistic overview of the recognition of long-chain phenolic compounds in UGTs, while the structure of the kaempferol complex elaborates the poor regioselective glycosylation of phenolic compounds with multiple possible glycosylation sites
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