Mannosidases are enzymes that catalyze the hydrolysis of terminal non-reducing α- or β-D-mannose residues in mannoglycosides. Moreover, α-Mannosidase is an important protease involved in glycoprotein synthesis and metabolism. In fact, α-Mannosidase exsists in eukaryotic cytoplasm, endoplasmic reticulum, golgi apparatus and lysosome.  Moreover, N-glycan modification process involves different types and functions of α-Mannosidase. Specifically, α-Mannosidase function is to prune mannose from N-glycan.Interestingly, α-Mannosidase divides exo mannosidase and endo mannosidase according to the enzymatic characteristics of mannosidase.

Here, we focus on the Class I α-Mannosidases inhibitor, Kifunensine.

Kifunensine is a potent and selective inhibitor of class I α-mannosidases in plants and animals. Notably, Kifunensine isolates from Actinomycete and can prevent α-mannosidases  from trimming mannose residues on glycoproteins, thus resulting in oligomannose-type glycans. Furthermore, Kifunensine inhibits endoplasmic reticulum (ER)-associated degradation (ERAD). According to the report, Kifunensine may represent a therapeutic approach for certain mutations by inhibiting α-Mannosidases.

In vivo, in T32-T59R-expressing mice, kifunensine treatment induces a further increase of calsequestrin 2 (CSQ2) protein expression. Similarly, kifunensine treatment in triadin KO mice is also able to increase CSQ2 expression. However, in the absence of kifunensine treatment, triadin KO mice exhibit epinephrine-induced polymorphic ventricular tachycardia (CPVT). That is to say, kifunensine treatment might slightly improve the cardiac phenotype only in the presence of unstable mutant triadin. Interestingly, the reason is that kifunensine induces a small increase in triadin expression. It’s worth noting that, kifunensine results in improved targeting and folding of CSQ2.

Taken together, Kifunensine is a selective class I α-mannosidases inhibitor. Kifunensine may be used for the research of cardiovascular disease.



[1]. Cacheux M, et al. Mol Ther. 2020 Jan; 28(1):171-179.

[2]. Xiong Y, et al. Int J Mol Sci. 2018 Mar; 19(3):890.