Abstract
The pseudo-glycosyltransferase VldE catalyzes non-glycosidic C-N coupling between an unsaturated cyclitol and a saturated aminocyclitol with the conservation of the stereochemical configuration of the substrates to form validoxylamine A 7′-phosphate, the biosynthetic precursor of the antibiotic validamycin A. To study the molecular basis of its mechanism, the three-dimensional structures of VldE from Streptomyces hygroscopicus subsp. limoneus was determined in apo form, in complex with GDP, in complex with GDP and validoxylamine A 7′-phosphate, and in complex with GDP and trehalose. The structure of VldE with the catalytic site in both an “open” and “closed” conformation is also described. With these structures, the preferred binding of the guanine moiety by VldE, rather than the uracil moiety as seen in OtsA could be explained. The elucidation of the VldE structure in complex with the entirety of its products provides insight into the internal return mechanism by which catalysis occurs with a net retention of the stereochemical configuration of the donated cyclitol.
Highlights
IntroductionGlycosyltransferases comprise one of the most numerous and diverse groups of enzymes in nature
Glycosyltransferases comprise one of the most numerous and diverse groups of enzymes in nature. They are responsible for the formation of oligo/polysaccharides, glycoproteins, glycolipids, and many other glycosylated natural products by transferring a sugar moiety from an activated donor sugar to a sugar acceptor
Our comparative bioinformatics studies suggest that among those reported as glycosyltransferases are pseudo-glycosyltransferases, which do not recognize sugars as substrates but rather catalyze the formation of non-glycosidic C-N bonds in the biosynthesis of C7N-aminocyclitol-containing natural products such as acarbose and validamycin A (Figure 1) [2,3,4]
Summary
Glycosyltransferases comprise one of the most numerous and diverse groups of enzymes in nature. They are responsible for the formation of oligo/polysaccharides, glycoproteins, glycolipids, and many other glycosylated natural products by transferring a sugar moiety from an activated donor sugar to a sugar (or non-sugar) acceptor. This abundant group of proteins consists of 92 families encoded by more than 83,400 genes [1]. An a-glucosidase inhibitor, has been proven useful in the treatment of type II insulin-independent diabetes, whereas validamycin A, a natural trehalase inhibitor, is an antifungal antibiotic that has long been used to protect crops from soil borne diseases such as rice sheath blight and the dumping-off of cucumber seedlings [5,6,7,8]
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