Enzymatic Glycosylation of Nonbenzoquinone Geldanamycin Analogs via Bacillus UDP-Glycosyltransferase

Abstract

c Geldanamycin (GM) is a naturally occurring anticancer agent isolated from several strains of Streptomyces hygroscopicus. However, its potential clinical utility is compromised by its severe toxicity and poor water solubility. For this reason, considerable efforts are under way to make new derivatives that have both good clinical efficacy and high water solubility. On the other hand, glycosylation is often a step that improves the water solubility and/or biological activity in many natural products of biosynthesis. Here, we report the facile production of glucose-conjugated nonbenzoquinone GM analogs using the Bacillus UDP-glycosyltransferase BL-C. Five aglycon substrates containing nonbenzoquinone aromatic rings were chosen to validate the in vitro glycosylation reaction. Putative glucoside compounds were determined through the presence of a product peak(s) and were also verified using LC/MS analyses. Further, the chemical structures of new glucoside compounds 6 and 7 were elucidated using spectroscopy data. These glucoside compounds showed a dramatic improvement in water solubility compared with that of the original aglycon, nonbenzoquinone GM.

Enzymatic Biosynthesis of Novel Resveratrol Glucoside and Glycoside Derivatives

“…AAU40842.1) from Bacillus licheniformis DSM 13, with a flexible donor and acceptor substrate profile was selected in order to synthesize glycodiversified resveratrol derivatives. YjiC has been shown to accept geldanamycin analogues (52), epothilone A (53), various flavonoids (54,55), chalcone (56), and isoflavonoids (57) as substrates for glucosylation. In this study, resveratrol was used as an acceptor substrate and various rare nucleotide diphosphate sugars were used as sugar donor substrates to produce glycodiversified resveratrol derivatives that have not been previously described.…”

Enzymatic Synthesis of Novel Phloretin Glucosides

“…According to the CAZy database (http://www .cazy.org/) (16,17,18), glycosyltransferase family 1 (GT1) proteins contain the UDP-glycosyltransferases that are common in all domains of life (19) and predominantly recognize small molecules as the sugar acceptors. A recent report showed that YjiC, a Bacillus licheniformis UDP-glycosyltransferase that falls in the GT1 family of proteins, can glycosylate at different hydroxyl positions of geldanamycin analogs (20). Here, we report the use of this glycosyltransferase for the biosynthesis of diverse phloretin glucosides in vitro and the subsequent application of YjiC for in vivo production of phloretin glucosides in an Escherichia coli mutant generating a cytoplasmic pool of UDP-glucose, since the YjiC-homologous glycosyltransferases from other Bacillus species were found to have flexible glycosyltransferase activities toward different flavonoid groups of compounds.…”

Enzymatic Synthesis of Novel Bavachinin Glucoside by UDP‐glycosyltransferase

“…10 Recently, UDP-glycosyltransferase (YjiC) from Bacillus have been used to synthesize some novel glucosides such as apigenin, 1 7-hydroxy-8-methoxy-flavone, 11 magnolol and honokiol, 12 and geldanamycin analogs. 13 Besides, YjiC have been reported to have highly flexible non-regiospecific glycosylation ability toward polyphenolic compounds. 14 In this report, we studied in vitro glycosylation of bavachinin using the YjiC, the structural elucidation of the bavachinin glucoside ( Figure 1), water-solubility determination, and the anti-proliferative effects on the four human tumor cell lines.…”