Cyclophellitol Explained

Cyclophellitol is a potent irreversible inhibitor of beta-glucosidases.^[1] It is a cyclitol mimic of beta-glucose with an epoxide group in place of the acetal group found in glucosides. When recognized, cyclophellitol undergoes an acid-catalyzed ring-opening addition reaction with the catalytic nucleophile of a retaining glycoside hydrolase.^[2] The resulting ester linkage cannot be hydrolyzed by the normal catalytic machinery of the enzyme, resulting in irreversible inhibition.

Cyclophellitol was originally isolated from a species of Phellinus mushroom found in Japan. The first total chemical synthesis of cyclophellitol was demonstrated by Tatsuta et al.^[3] Synthetic derivatives of cyclophellitol have been used for the detection of enzymes such as glucocerebrosidase, deficiency of which results in Gaucher's disease.^[4]

Notes and References

1. Atsumi, S. et al. (1990) ‘Production, isolation and structure determination of a novel β-glucosidase Inhibitor, cyclophellitol, from phellinus sp’, The Journal of Antibiotics. Japan Antibiotics Research Association, 43(1), pp. 49–53. doi: 10.7164/antibiotics.43.49.
2. Gloster, T. M., Madsen, R. and Davies, G. J. (2007) ‘Structural basis for cyclophellitol inhibition of a β-glucosidase’, Organic and Biomolecular Chemistry. The Royal Society of Chemistry, 5(3), pp. 444–446. doi: 10.1039/b616590g.
3. Tatsuta, K. et al. (1991) ‘Syntheses and Enzyme Inhibiting Activities of Cyclophellitol Analogs’, Journal of Antibiotics. Japan Antibiotics Research Association, 44(8), pp. 912–914. doi: 10.7164/antibiotics.44.912.
4. Witte, M. D. et al. (2010) ‘Ultrasensitive in situ visualization of active glucocerebrosidase molecules’, Nature Chemical Biology. Nature Publishing Group, 6(12), pp. 907–913. doi: 10.1038/nchembio.466.