myo-Inositol Polyphosphates and Their Role in Cellular Metabolism

Biosynthesis of aminocyclitol-aminoglycoside antibiotics and related compounds

“…limoneus, respectively. The results indicated that 2-epi-5-epi-valiolone (142) is the common precursor for the biosynthesis of the core C 7 -cyclitol moieties in acarbose (11) and validamycin A (12). [130][131][132] In the case of 12, besides 142, 5-epivaliolone (143), valienone (144) and validone (145) were also incorporated (Fig.…”

“…Two groups of biosynthetic pathways have been characterized in depth and include aminoglycosides originating from i) the myo-inositol pathway, e.g., streptomycin (6) and hygromycin A (8), and ii) the 2deoxy-scyllo-inosose pathway, e.g., gentamicin (2), kanamycin (3), and butirosin (10). A third group of aminocyclitol/aminoglycoside natural products represents compounds that contain a C 7 N aminocyclitol moiety, exemplified by the potent a-glucosidase inhibitor acarbose (11) and the antifungal-antibiotic validamycin A (12). Acarbose is one of a new generation of anti-type II insulinindependent antidiabetic drugs available on the market, whereas validamycin has been widely used in Asia as a crop protectant.…”

“…The third prominent class of aminocyclitol natural products contains a C 7 N aminocyclitol unit in their core structure. Members of this family of natural products include the a-glucosidase inhibitors acarbose (11), the oligostatins (e.g., 137), and the trestatins (e.g., 138), the trehalase inhibitor validamycin A (12), the antibiotic pyralomicin 1a (139), and the antitumor agent cetoniacytone (140) (Fig. 15).…”

“…Their chemical structures most commonly contain an unsaturated aminocyclitol unit, valienamine (141), although in some compounds modified forms of valienamine are present instead. The antidiabetic agent acarbose (11) and the antifungal antibiotic validamycin A (12) have become prominent members of this family of natural products due to their significant biomedical and agricultural uses. 11 is one of the components in a complex mixture of pseudooligosaccharides produced by Actinoplanes strain SE 50/110 with potent inhibitory activity against various sugar hydrolytic enzymes.…”

“…17 and Table 4). 135 In vivo inactivation of the putative glycosyltransferase gene (valG) abolished the final attachment of glucose for validamycin (12) production, and resulted in the accumulation of the precursor, validoxylamine A (162) (Scheme 14). 135 Complementation with valG restored the normal production of validamycin A, and in vitro enzymatic assays using the recombinant ValG protein demonstrated the glycosylation of validoxylamine A to validamycin A.…”