Cyclodextrins (CDs) are cyclic oligosaccharides commonly comprised of six (α-CD), seven (β-CD), or eight (γ-CD) glucopyranose units, which are produced by degradation of starch and its derivatives by cyclodextrin glycosyltransferases (EC 2.4.1.19, CGTase). CD have a truncated conical structure with a hydrophilic outside and a hydrophobic inner cavity, capable of complexation with guest molecules and widely applied in food, medicine, cosmetics, agriculture, and other fields. For example, CDs are used in foods to protect oxygen/light/heat-sensitive ingredients, increase solubility of insoluble ingredients, mask undesirable flavors, and control release of food components (Astray et al., 2009). CDs are moreover used in drugs as solubilizers, diluents, or tablet ingredients to increase bioavailability (Loftsson and Duchene, 2007). In the chemical industry, CDs can serve to improve reaction selectivity and separation of products (Schneiderman and Stalcup, 2000). These applications are based on the interaction between CDs and guest molecules.

Beyond the above interaction, CDs interact with different glycoside hydrolases (GHs) and affect their catalytic processes. GHs catalyze hydrolysis of glycosidic linkages in glycosides and can also form new products by reacting with other glycosides or water molecules as acceptors (Fig. 1) (Davies and Henrissat, 1995), attracting much attention both in academic research and in industry. Among GHs, starch-active enzymes such as α-amylase (EC 3.2.1.1) (Farooq et al., 2021), pullulanase (EC 3.2.1.41) (Hii et al., 2012), and CGTase (Qi and Zimmermann, 2005) have for decades been applied in bulk industrial production (Miao et al., 2018). Yet the catalytic process of these enzymes is sensitive to substrate/product inhibition. Other GHs such as cyclodextrinase (EC 3.2.1.54, CDase) are still emerging due to their less well understood reaction mechanism, poor recombinant production, insufficient stability etc. There is a need to clarify interactions between enzymes and ligands such as substrate/products and the significance for regulation of enzyme activity, exploration of enzyme mechanisms, and desired engineering of the enzymes.

CDs have been shown to be important in regulating enzyme catalysis. Firstly, CDs directly interact with several GHs as products (Biwer et al., 2002), substrates (Ji et al., 2019), inhibitors (Yu et al., 2011), and activators. Therefore, CDs can serve as model ligands to explore functional amino acid residues, catalytic mechanisms and other characteristics of enzymes, which can provide key structural basis for rational enzyme engineering. In addition to direct interaction with enzymes, CDs can affect enzymatic catalytic processes indirectly by solubilizing substrates (Borner et al., 2014), separating products (Flick and Bloch, 1974), and improving enzyme stability (Wang et al., 2018a, Wang et al., 2018b). CDs are also applied for enzyme purification by affinity chromatography (Rodriguez et al., 2020; Schneiderman and Stalcup, 2000). Furthermore, based on CD's unique cavity accommodating guest molecules and the exposed external hydroxyl groups, CDs have been developed as artificial enzyme mimetics (Aghahosseini and Ramazani, 2016). This enables CDs to make an essential leap from ligand to catalyst. In this review, we cover the diverse roles of CD in catalytic processes of GHs to provide guidance for further research between these enzymes and ligands.