Glycosyltransferases involved in the biosynthesis of bacterial secondary metabolites may be useful for the generation of sugar-modified analogues of bioactive natural products. Some glycosyltransferases have relaxed substrate specificity, and it has been assumed that promiscuity is a feature of the class. As part of a program to explore the synthetic utility of these enzymes, we have analyzed the substrate selectivity of glycosyltransferases that attach similar 2-deoxy-L-sugars to glycopeptide aglycons of the vancomycin-type, using purified enzymes and chemically synthesized TDP beta-2-deoxy-L-sugar analogues. We show that while some of these glycopeptide glycosyltransferases are promiscuous, others tolerate only minor modifications in the substrates they will handle. For example, the glycosyltransferases GtfC and GtfD, which transfer 4-epi-L-vancosamine and L-vancosamine to C-2 of the glucose unit of vancomycin pseudoaglycon and chloroorienticin B, respectively, show moderately relaxed donor substrate specificities for the glycosylation of their natural aglycons. In contrast, GtfA, a transferase attaching 4-epi-L-vancosamine to a benzylic position, only utilizes donors that are closely related to its natural TDP sugar substrate. Our data also show that the spectrum of donors utilized by a given enzyme can depend on whether the natural acceptor or an analogue is used, and that GtfD is the most versatile enzyme for the synthesis of vancomycin analogues.

2004-03-30·Proceedings of the National Academy of Sciences1区 · 综合性期刊

Characterization of a regiospecific epivancosaminyl transferase GtfA and enzymatic reconstitution of the antibiotic chloroeremomycin

1区 · 综合性期刊

Article

作者: Oberthür, Markus ; Walsh, Christopher T. ; Tao, Junhua ; Kahne, Daniel ; Lu, Wei ; Leimkuhler, Catherine

Chloroeremomycin, a vancomycin family glycopeptide antibiotic has three sugars, one d -glucose and two l -4- epi -vancosamines, attached to the crosslinked heptapeptide backbone by three glycosyltransferases, GtfA, -B, and -C. Prior efforts have revealed that GtfB and -C in tandem build an epivancosaminyl-1,2-glucosyldisaccharide chain on residue 4 of the aglycone; however, the characterization of GtfA and glycosylation sequence of chloroeremomycin have been lacking. Here, we report the expression and purification of GtfA, as well as synthesis of its sugar donor, 2′-deoxy-thymidine 5′-diphosphate (dTDP)-β- l -4- epi -vancosamine. GtfA transfers 4- epi -vancosamine from the chemically synthesized dTDP-4- epi -vancosamine to the β-OH-Tyr 6 residue of the aglycone, preferentially after GtfB action, to generate chloroorienticin B. With the preferred kinetic order of GtfB, then GtfA, then GtfC established, we have succeeded in reconstitution of chloroeremomycin from the heptapeptide aglycone by the sequential actions of the three enzymes.

2002-11-01·Bioorganic & Medicinal Chemistry Letters4区 · 医学

Novel semi-synthetic glycopeptide antibiotics active against methicillin-resistant staphylococcus aureus (MRSA) and vancomycin-resistant Enterococci (VRE): doubly-modified water-soluble derivatives of chloroorienticin B

4区 · 医学

Article

作者: Yasuhiro Nishitani ; Tadashi Munekage ; Tatsuro Yasukata ; Yukitoshi Narukawa ; Yukihito Sumino ; Osamu Yoshida

A series of N-alkylated and aminomethylated derivatives of chloroorienticin B, a vancomycin-related glycopeptide antibiotic, were synthesized. Doubly-modified derivatives having both hydrophobic and hydrophilic substituents exhibited potent antibacterial activity against MRSA and VRE along with considerable water-solubility.

100 项与 Chloroorienticin B 相关的药物交易

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


AACR2014	N/A	非小细胞肺癌	-	Cucurbitacin B	範繭鹹餘夢夢觸鬱艱膚(憲鏇齋築衊襯壓製醖齋) = 鬱鏇壓窪築構壓憲顧構蓋願鹹壓淵觸網襯醖膚 (餘獵鏇積醖鹹衊遞鏇簾 )	积极	2014-10-01
				Cucurbitacin B (Control (normal human bronchial epithelial cells))	鹽鑰願窪餘鏇鹽廠艱選(齋積顧膚壓構夢繭構襯) = 鹽願願艱醖鬱鏇獵簾窪壓淵壓觸構顧醖廠繭獵 (鏇艱鏇艱醖構鹽網窪壓 )
AACR2010	N/A	乳腺癌	-	Cucurbitacin B	糧膚顧築憲廠觸艱簾鏇(襯觸窪夢獵膚窪壓顧鹹) = 選醖窪醖窪鑰壓膚築鹹願顧鏇夢顧範積獵獵顧 (鏇獵網鑰範艱餘願鹹範 )	-	2010-04-15
				Dihydrocucurbitacin B	糧膚顧築憲廠觸艱簾鏇(襯觸窪夢獵膚窪壓顧鹹) = 鹹顧夢繭顧壓鹹顧糧鏇願顧鏇夢顧範積獵獵顧 (鏇獵網鑰範艱餘願鹹範 )