Molecular Basis for Trehalase Inhibition Revealed by the Structure of Trehalase in Complex with Potent Inhibitors

Abstract

Strong inhibitions: The inhibition of trehalases, enzymes which hydrolyze the disaccharide trehalose, is a target for novel antibiotic insecticides. The structures (see picture; C black, N blue, O red, S yellow) of a trehalase in complex with validoxylamine A (yellow) and 1‐thiatetrazolin (blue) reveal that the inhibitors tightly bind to the enzyme through hydrogen bonds.

Trehalases: A neglected carbon metabolism regulator?

“…8 In addition, using the trehalase crystallographic structure of (PDB code: 2WYN) we modeled the tridimensional structure from full sequences of all trehalases (33) reported. 5,10 The trehalase deduced structures from bacterial, animal, plant and fungi (neutral and acid) origin yielded a RMSD average of 0.062 Å, 0.079 Å, 0.078 Å, 0.080 Å and 0.076 Å, respectively ( Fig. 2A).…”

“…2B). 5 Additionally, we performed the maximum likelihood analysis of natural selection, on a codon-bycodon basis, for all trehalase sequences, to determine a marked trend for synonymous substitutions for the catalytic residues and trehalase signatures 1 and 2 (Fig. 2C).…”

“…3 In addition, the distribution 4 of six consensus discrete motifs, besides the catalytic domain, were found. [5][6][7][8][9] These motifs are: a transmembrane span (LFF FFF FFL CFS FTT SML); a cAMP-dependent phosphorylation site (RRXS); an EF-like Ca 2+ -binding motif (DTX GDX QIT IXD); two trehalase signature motifs 1 and 2, (PGG RFX EXY XWD XY) and (QWDXPX[G/A]W[P/A/S]P), respectively; and the glycosylphosphatidylinositol (GPI) membrane anchor motif (CRT NYG YSA A). The catalytic residues are distributed from the trehalase signature 1 to the C-terminal end.…”

Structural Similarity between a Starch-hydrolyzing Enzyme and an N-Glycan-Hydrolyzing Enzyme: Exohydrolases Cleaving α-1,X-Glucosidic Linkages to Produce β-Glucose

“…The enzyme also weakly hydrolyzes trehalose, maltose, and maltooligosaccharides, suggesting that the substrate specificity of E. coli YgjK is low (9). The catalytic residues of GH15 are identified as 2 glutamic acid residues, while in the case of GH37 and GH63, an aspartic acid residue and a glutamic acid residue function as the general acid and the general base, respectively, but the positions of the catalytic residues are highly conserved (8,9). Superimposition studies of GH37 (E. coli Tre37A) and GH63 (E. coli YgjK and T. thermophilus uncharacterized protein TTHA0978) show that the main chains of their catalytic (α/α) 6 barrel domains are overlain (Fig.…”

“…1C) (7), and trehalase (EC 3.2.1.28; Fig. 1D) (8), which hydrolyzes α-1,4-, α-1,6-, and α-1,1-glucosidic linkages, respectively, and Escherichia coli YgjK (Fig. 1E) (9), an enzyme that hydrolyzes the α-1,3-glucosidic linkage of nigerose.…”