An overall look at insect chitin deacetylases: Promising molecular targets for developing green pesticides

Abstract

Chitin deacetylase (CDA) is a key enzyme involved in the modification of chitin and plays critical roles in molting and pupation, which catalyzes the removal of acetyl groups from N-acetyl-D-glucosamine residues in chitin to form chitosan and release acetic acid. Defects in the CDA genes or their expression may lead to stunted insect development and even death. Therefore, CDA can be used as a potential pest control target. However, there are no effective pesticides known to target CDA. Although there has been some exciting research progress on bacterial or fungal CDAs, insect CDA characteristics are less understood. This review summarizes the current understanding of insect CDAs, especially very recent advances in our understanding of crystal structures and the catalytic mechanism. Progress in developing small-molecule CDA inhibitors is also summarized. We hope the information included in this review will help facilitate new pesticide development through a novel action mode, such as targeting CDA.

Keywords: chitin deacetylases; inhibitor; insect; structure.

Fig. 1. The catalytic action of chitin deacetylase.¹⁾

Fig. 2. A phylogenetic tree of putative CDAs from different insects.³⁰⁾

Fig. 3. The acid/base catalytic mechanism in VcCDA involving an oxyanion intermediate stabilized by a metal cation.³⁵⁾ First, a metal-bound water molecule is activated by the general base residue (Asp39) to form a tetrahedral oxyanion intermediate. The negative charge developed at the carbonyl oxygen atom is stabilized by both metal coordination and the main chain nitrogen atom of Tyr169. Second, the nitrogen group of the intermediate is protonated by the general acid residue (His295) to assist in the cleavage of a C–N bond, generating a free amine in the de-N-acetylated product and releasing acetate.

Fig. 4. Schematic representations of the mode of (GlcNAc)₃ binding to BmCDA8.³³⁾

Fig. 5. Conserved catalytic motifs 1–5 of the CE4 family. (Left) Spatial disposition in the 3D active-site structure; (Right) Motif sequences for some CE4 family enzymes.³⁸⁾

Fig. 6. Structural comparison of the topological structure and substrate-binding cleft among BmCDAs, ArCE4A, and VcCDA.³³⁾

Fig. 7. Several inhibitors of CE4. Bc1974 means Bacillus cereus peptidoglycan N-acetylglucosamine deacetylase, PgdA means Streptococcus pneumoniae peptidoglycan de-N-acetylase and PgaB means Escherichia coli exopolysaccharide deacetylase.