Natural Product Glycorandomization

Yang, Jie; Hoffmeister, Dirk; Liu, Lesley; Fu, Xun; Thorson, Jon S.

doi:10.1002/chin.200421300

Cited by 8 publications

(8 citation statements)

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“…attached to target molecules can mediate drug targeting and biological activity. Thus, enzymes that have a broad substrate range and less regioselectivity will be useful for altering glycosylation patterns on secondary metabolites (Méndez & Salas, 2001;Yang et al, 2004). As far as we know, BcGT-1 is the first microbial enzyme that carries out glycosylation reactions on flavonoids.…”

Section: Modification Of Flavonoids With the Recombinant Bcgt-1mentioning

confidence: 99%

Glycosylation of flavonoids with a glycosyltransferase fromBacillus cereus

Kim

Ahn

2006

FEMS Microbiology Letters

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Microbial glycosyltransferases can convert many small lipophilic compounds such as phenolics, terpenoids, cyanohydrins and alkaloids into glycons using uridine-diphosphate-activated sugars. The main chemical functions of glycosylation processes are stabilization, detoxification and solubilization of the substrates. The gene encoding the UDP-glycosyltransferase from Bacillus cereus, BcGT-1, was cloned by PCR and sequenced. BcGT-1 was expressed in Escherichia coli BL21 (DE3) with a his-tag and purified using a His-tag affinity column. BcGT-1 could use apigenin, genistein, kaempferol, luteolin, naringenin and quercetin as substrates and gave two reaction products. The enzyme preferentially glycosylated at the 3-hydroxyl group, but it could transfer a glucose group onto the 7-hydroxyl group when the 3-hydroxyl group was not available. The reaction products made by biotransformation of flavonoids with E. coli expressing BcGT-1 are similar to those produced with the purified recombinant enzyme. Thus, this work provides a method that might be useful for the biosynthesis of flavonoid glucosides and for the glycosylation of related compounds.

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Section: Modification Of Flavonoids With the Recombinant Bcgt-1mentioning

confidence: 99%

Glycosylation of flavonoids with a glycosyltransferase fromBacillus cereus

Kim

Ahn

2006

FEMS Microbiology Letters

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“…Therefore, diversification of natural product glycosylation is considered as a basis of current drug developments (Blanchard and Thorson, 2006;Salas and Mendez, 2007;Thibodeaux et al, 2007). Glycosyltransferases (GTs) catalyze the transfer of a sugar moiety from a nucleotide activated sugar to aglycone, accordingly, the promiscuities of GTs perform a significant function in the glycorandomization of therapeutically important natural products (Floss, 2001;Fu et al, 2003;Leadlay, 1997;Melancon et al, 2006;Mendez and Salas, 2001;Rupprath et al, 2005;Salas and Mendez, 2007;Yang et al, 2004). Although the successful transfer of a variety sugars onto glycopeptides (Losey et al, , 2002 and polyketides (Blanchard and Thorson, 2006) has been previously achieved, stringent substrate specificity of GTs still remains as a severe limitation to natural product diversification Floss, 2006;Zhang et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

Expanding substrate specificity of GT‐B fold glycosyltransferase via domain swapping and high‐throughput screening

Park

Sohng

et al. 2008

Biotech & Bioengineering

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Glycosyltransferases (GTs) are crucial enzymes in the biosynthesis and diversification of therapeutically important natural products, and the majority of them belong to the GT-B superfamily, which is composed of separate N- and C-domains that are responsible for the recognition of the sugar acceptor and donor, respectively. In an effort to expand the substrate specificity of GT, a chimeric library with different crossover points was constructed between the N-terminal fragments of kanamycin GT (kanF) and the C-terminal fragments of vancomycin GT (gtfE) genes by incremental truncation method. A plate-based pH color assay was newly developed for the selection of functional domain-swapped GTs, and a mutant (HMT31) with a crossover point (N-kanF-669 bp and 753 bp-gtfE-C) for domain swapping was screened. The most active mutant HMT31 (50 kDa) efficiently catalyzed 2-DOS (aglycone substrate for KanF) glucosylation using dTDP-glucose (glycone substrate for GtfE) with k(cat)/K(m) of 162.8 +/- 0.1 mM(-1) min(-1). Moreover, HMT31 showed improved substrate specificity toward seven more NDP-sugars. This study presents a domain swapping method as a potential means to glycorandomization toward various syntheses of 2-DOS-based aminoglycoside derivatives.

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“…any secondary metabolites found in nature exist as glycones (26). Subtle alteration of the sugars in natural products could change their molecular and cellular specificity, leading to changes in pharmacological properties (16).…”

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confidence: 99%

Production of a Novel Quercetin Glycoside through Metabolic Engineering of Escherichia coli

Yoon

Kim

Lee

et al. 2012

Appl Environ Microbiol

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ABSTRACTMost flavonoids exist as sugar conjugates. Naturally occurring flavonoid sugar conjugates include glucose, galactose, glucuronide, rhamnose, xylose, and arabinose. These flavonoid glycosides have diverse physiological activities, depending on the type of sugar attached. To synthesize an unnatural flavonoid glycoside,Actinobacillus actinomycetemcomitansgenetll(encoding dTDP-6-deoxy-l-lyxo-4-hexulose reductase, which converts the endogenous nucleotide sugar dTDP-4-dehydro-6-deoxy-l-mannose to dTDP-6-deoxytalose) was introduced intoEscherichia coli. In addition, nucleotide-sugar dependent glycosyltransferases (UGTs) were screened to find a UGT that could use dTDP-6-deoxytalose. Supplementation of this engineered strain ofE. coliwith quercetin resulted in the production of quercetin-3-O-(6-deoxytalose). To increase the production of quercetin 3-O-(6-deoxytalose) by increasing the supplement of dTDP-6-deoxytalose inE. coli, we engineered nucleotide biosynthetic genes ofE. coli, such asgalU(UTP-glucose 1-phosphate uridyltransferase),rffA(dTDP-4-oxo-6-deoxy-d-glucose transaminase), and/orrfbD(dTDP-4-dehydrorahmnose reductase). The engineeredE. colistrain produced approximately 98 mg of quercetin 3-O-(6-deoxytalose)/liter, which is 7-fold more than that produced by the wild-type strain, and the by-products, quercetin 3-O-glucose and quercetin 3-O-rhamnose, were also significantly reduced.

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Natural Product Glycorandomization

Abstract: For Abstract see ChemInform Abstract in Full Text.

Cited by 8 publications

References 1 publication

Glycosylation of flavonoids with a glycosyltransferase fromBacillus cereus

Glycosylation of flavonoids with a glycosyltransferase fromBacillus cereus

Expanding substrate specificity of GT‐B fold glycosyltransferase via domain swapping and high‐throughput screening

Production of a Novel Quercetin Glycoside through Metabolic Engineering of Escherichia coli

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