Genetically engineered production of 1,1′-bis-valienamine and validienamycin in Streptomyces hygroscopicus and their conversion to valienamine

Abstract

The antifungal agent validamycin A is an important crop protectant and the source of valienamine, the precursor of the antidiabetic drug voglibose. Inactivation of the valN gene in the validamycin A producer, Streptomyces hygroscopicus subsp. jinggangensis 5008, resulted in a mutant strain that produces new secondary metabolites 1,1′-bis-valienamine and validienamycin. The chemical structures of 1,1′-bis-valienamine and validienamycin were elucidated by 1D and 2D NMR spectroscopy in conjunction with mass spectrometry and bioconversion employing a glycosyltransferase enzyme, ValG. 1,1′-bis-Valienamine and validienamycin exhibit a moderate antifungal activity against Pellicularia sasakii. Chemical degradation of 1,1′-bis-valienamine using N-bromosuccinimide followed by purification of the products with ion-exchange column chromatography only resulted in valienamine, whereas parallel treatments of validoxylamine A, the aglycon of validamycin A, resulted in an approximately 1:1 mixture of valienamine and validamine, underscoring the advantage of 1,1′-bis-valienamine over validoxylamine A as a commercial source of valienamine.

Biosynthesis and metabolic engineering of pseudo-oligosaccharides

“…Interestingly, in A. mirum , valienone 7-phosphate is formed through a different route involving 2-epi-valiolone (42) (Figure 4). Valienone 7-phosphate serves as a common precursor for both the unsaturated (valienamine) and the saturated (validamine) pseudosugar units (30), where the saturated pseudosugar is derived from the unsaturated one by the zinc-dependent dehydrogenase ValN (43).…”

Biosynthesis of nitrogen-containing natural products, C7N aminocyclitols and bis-indoles, from actinomycetes

“…ValN was predicted to catalyze a double-bond reduction to generate validamine 7-phosphate. 36) The details of the coupling of the two cyclitol units (GDP-valienol and validamine 7-phosphate) are discussed in section II. After the formation of validoxylamine A, ValG catalyzes the O-glycosyltransferase reaction to produce validamycin A.…”

Update on Bioactive Molecules of Actinomycetes

“…Valielamine, a precursor of voglibose and a new aminocyclitol, isolated from the fermentation broth of Streptomyces hygroscopicus subspecies limoneus. It has more potent a-glucosidase inhibitory activity against porcine intestinal sucrase, maltase and isomaltase than valienamine, validamine and hydroxylvalidamine which were reported as building blocks of validamycins and microbial oligosaccharide a-glucosidase inhibitors 57 .…”