Incorporation of glucose analogs by GtfE and GtfD from the vancomycin biosynthetic pathway to generate variant glycopeptides
Incorporation of glucose analogs by GtfE and GtfD from the vancomycin biosynthetic pathway to generate variant glycopeptides
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DOI：
10.1016/s1074-5521(02)00270-3
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发表时间：
2002-12-01
影响因子：
--
通讯作者：
Walsh, CT
中科院分区：
文献类型：
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作者：
Losey, HC;Jiang, JQ;Walsh, CT
通过万古霉素途径糖基转移酶 GtfE 和 GtfD 的串联作用，制备了糖肽抗生素万古霉素和替考拉宁的类似物，其中二糖的一个或两个糖部分发生了改变。 TDP-脱氧葡萄糖和UDP/TDP-氨基葡萄糖的所有四种区域异构体（2-、3-、4-、6-）主要通过D-吡喃葡萄糖基-1-磷酸胸苷酰转移酶E-p的作用来制备。 GTfE 将脱氧葡萄糖或氨基葡萄糖转移到万古霉素和替考拉宁糖苷配基支架的 4-羟基苯基甘氨酸的 4-OH 上。动力学分析表明，与天然底物 UDP/TDP-葡萄糖相比，2-、3-、4-和 6-氨基葡萄糖通过 GtfE 转移，k(cat) 仅下降 4 至 30 倍，并且对 K-m 没有影响，表明其制备用途。下一个酶，GtfD，可以利用变体葡萄糖肽作为 L-4-表-万古胺转移的底物。这些变体糖肽中的氨基糖部分引入了酰化或还原烷基化位点。
Analogs of the glycopeptide antibiotics vancomycin and teicoplanin with alterations in one or both sugar moieties of the disaccharide have been prepared by tandem action of the vancomycin pathway glycosyl-transferases GtfE and GtfD. All four regioisomers (2-, 3-,4-,6-) of TDP-deoxyglucoses and UDP/TDP-amino-glucoses were prepared, predominantly by action of D-glucopyranosyl-1-phosphate thymidylyltransferase, E-p. GtfE transferred the deoxyglucoses or aminoglucoses onto the 4-OH of 4-hydroxyphenylglycine of both the vancomycin and teicoplanin aglycone scaffolds. Kinetic analysis indicated the 2-, 3-, 4-, and 6-amino-glucoses were transferred by GtfE with only a 4- to 30-fold drop in k(cat) and no effect on K-m compared to the native substrate, UDP/TDP-glucose, suggesting preparative utility. The next enzyme, GtfD, could utilize the variant glucosyl-peptides as substrates for transfer of L-4-epi-vancosamine. The aminosugar moieties in these variant glycopeptides introduce sites for acylation or reductive alkylation.