Glycoside hydrolase family 18 and 20 enzymes are novel targets of the traditional medicine berberine

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 ␤-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 (OfHex1), with K i values of 12 and 8.5 M, respectively. Co-crystallization of berberine and its analog SYSU-1 in complex with OfHex1 revealed that the positively charged conjugate plane of berberine formsstacking 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 (HsHexB), human GH18 chitinase (HsCht and acidic mammalian chitinase), and insect GH18 chitinase (OfChtI). Besides GH18 and GH20 enzymes, berberine was shown to weakly inhibit human GH84 O-GlcNAcase (HsOGA) and Saccharomyces cerevisiae GH63 ␣-glucosidase I (ScGluI). By analyzing the published crystal structures, berberine was revealed to bind with its targets in an identical mechanism, namely viastacking 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. Berberine is an isoquinoline quaternary alkaloid widely distributed in the root, stem, and bark of plants from the Berberis and Coptis families, such as Berberis aristata, Berberis aquifolium, Berberis vulgaris, Coptis chinesis, Coptis japonica, and Coptis rhizome (1-3). Berberine has been used for more than 3,000 years in Ayurvedic, Chinese, and Middle-Eastern folk medicine for its antimicrobial, antiprotozoal, antidiarrheal, and antitrachomatic activities (1-3). With the development of modern biomedicine, berberine has been revealed to have a very wide range of pharmacological properties, including anticancer, antidiabetic, antidepressant, antihyperlipidemic, and antihypertensive activities (4-8). Moreover, berberine has also been revealed to have potential applications in agriculture for its antifungal, insecticidal, and herbicidal activities (9-11). Corresponding to its multispectrum activities, several molecular targets of berberine, such as glycogen synthase kinase, calmodulin kinase, matrix metalloprotease, acetylcholinesterase, butyrylcholinesterase, monoamine oxidase, DNA topoisomerase, cyclin, and transcriptional factor p53 (12-18), have been discovered. Glycoside hydrolase family 20 ␤-N-acetyl-D-hexosaminidase (GH20 Hex) 3 catalyzes the removal of N-acetyl-D-glucosamine (GlcNAc) or N-acetyl-D-galactosamine (GalNAc) fr...

Review on Structures of Pesticide Targets

“…In addition, insect chitinases play crucial roles in chitinous tissues and other physiological processes, and thus are new and potent molecular targets. The crystal structure of insect beta-N-acetyl-D-hexosaminidase OfHex1 [ 50 ] and the co-crystal structures with its inhibitors, TMG-chitotriomycin ( Figure 2 D) [ 50 ], PUGNAc [ 51 ], and berberine [ 52 ], were successfully solved. OfHex1 is an enzyme that linked to an “open-close” mechanism at the entrance of the active site; the active pocket size of OfHex1 to TMG-chitotriomycin was Trp 490 , the active pocket size of OfHex1 to PUGNAc was Val 327 , and the active pocket size of OfHex1 to berberine was Trp 322 , Trp 483 , Val 484 , which contributes to its inhibitory activity.…”

Berberine attenuates XRCC1‐mediated base excision repair and sensitizes breast cancer cells to the chemotherapeutic drugs

“…Berberine (BBR) is an isoquinoline alkaloid extracted from the rhizomes of Coptis, which displays multiple biochemical functions and anti‐microbial and anti‐inflammatory activities . BBR also exhibits anti‐cancer activities through suppressing cell proliferation and inducing tumour cell apoptosis .…”

“…Berberine (BBR) is an isoquinoline alkaloid extracted from the rhizomes of Coptis, which displays multiple biochemical functions and anti-microbial and anti-inflammatory activities. 14,15 BBR also exhibits anti-cancer activities through suppressing cell proliferation and inducing tumour cell apoptosis. [16][17][18][19][20][21][22] BBR reportedly directly binds with DNA, radio-sensitizes lung and oesophageal cancer cells and sensitizes ovarian cancer cells to cisplatin and PARP inhibitors.…”

Structural dissection reveals a general mechanistic principle for group II chitinase (ChtII) inhibition

“…In our previous works, we observed that compounds bearing a large conjugated plane were likely to be potent inhibitors of GH18 chitinase (27,30). In this study, exploiting our previously reported two constructs of OfChtII (OfChtII-C1, residues 1606 -1992; OfChtII-C2, residues 2056 -2438) (8), we screened the compound library of our lab which contains a mass of compounds with a large conjugated plane and obtained four potent inhibitors.…”

“…Cyclic peptide-based inhibitors, such as argifin, argadin, and their derivatives, mimic the carbohydrate-protein interactions (16 -21). By virtual screening, other inhibitors were also obtained, including methylxanthine derivatives (22)(23)(24), closantel derivatives (25,26), berberine (27), styloguanidine (28) and psammaplins (29). These compounds exhibit inhibitory activities at nanomolar to millimolar levels.…”