Download MendeleyGlycoside hydrolase family 18 and 20 enzymes are novel targets of the traditional medicine berberine.
Duan, Y., Liu, T., Zhou, Y., Dou, T., Yang, Q.(2018) J Biol Chem 293: 15429-15438
- PubMed: 30135205
- DOI: https://doi.org/10.1074/jbc.RA118.004351
- Primary Citation of Related Structures:
5Y0V, 5Y1B - PubMed Abstract:
Berberine is a traditional medicine that has multiple medicinal and agricultural applications. However, little is known about whether berberine can be a bioactive molecule toward carbohydrate-active enzymes, which play numerous vital roles in the life process. In this study, berberine and its analogs were discovered to be competitive inhibitors of glycoside hydrolase family 20 β- N -acetyl-d-hexosaminidase (GH20 Hex) and GH18 chitinase from both humans and the insect pest Ostrinia furnacalis Berberine and its analog SYSU-1 inhibit insect GH20 Hex from O. furnacalis ( Of Hex1), with K i values of 12 and 8.5 μm, respectively. Co-crystallization of berberine and its analog SYSU-1 in complex with Of Hex1 revealed that the positively charged conjugate plane of berberine forms π-π stacking interactions with Trp 490 , which are vital to its inhibitory activity. Moreover, the 1,3-dioxole group of berberine binds an unexplored pocket formed by Trp 322 , Trp 483 , and Val 484 , which also contributes to its inhibitory activity. Berberine was also found to be an inhibitor of human GH20 Hex ( Hs HexB), human GH18 chitinase ( Hs Cht and acidic mammalian chitinase), and insect GH18 chitinase ( Of ChtI). Besides GH18 and GH20 enzymes, berberine was shown to weakly inhibit human GH84 O- GlcNAcase ( Hs OGA) and Saccharomyces cerevisiae GH63 α-glucosidase I ( Sc GluI). By analyzing the published crystal structures, berberine was revealed to bind with its targets in an identical mechanism, namely via π-π stacking and electrostatic interactions with the aromatic and acidic residues in the binding pockets. This paper reports new molecular targets of berberine and may provide a berberine-based scaffold for developing multitarget drugs.
Organizational Affiliation:
From the State Key Laboratory of Fine Chemical Engineering, School of Life Science and Biotechnology and School of Software, Dalian University of Technology, Dalian 116024.
