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Glycosyltransferases involved in the biosynthesis of glycopeptide antibiotics.

紀錄類型:	書目-電子資源 : Monograph/item
正題名/作者:	Glycosyltransferases involved in the biosynthesis of glycopeptide antibiotics.
作者:	Losey, Heather Christina.
面頁冊數:	166 p.
附註:	Adviser: Christopher T. Walsh.
附註:	Source: Dissertation Abstracts International, Volume: 64-01, Section: B, page: 0190.
Contained By:	Dissertation Abstracts International64-01B.
標題:	Chemistry, Biochemistry.
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3076905
ISBN:	0493975772

Glycosyltransferases involved in the biosynthesis of glycopeptide antibiotics.
Losey, Heather Christina.

Glycosyltransferases involved in the biosynthesis of glycopeptide antibiotics. [electronic resource] - 166 p.

Adviser: Christopher T. Walsh.

Thesis (Ph.D.)--Harvard University, 2003.

Glycosyltransferase genes were cloned from glycopeptide-producing strains of chloroeremomycin (GtfA, GtfB, GtfC), vancomycin (GtfD, GtfE), and balhimycin (bGtfA). The purified glycosyltransferases were then characterized for activity. GtfB and GtfE transferred glucose from UDP-glucose to the natural acceptor substrate, vancomycin aglycone, and GtfE also recognized the teicoplanin aglycone. GtfC and GtfD transferred 4-epi-vancosamine from UDP-4- epi-vancosamine to the vancomycin pseudoaglycone making epivancomycin. In tandem, GtfE and GtfD synthesized a novel hybrid teicoplanin/vancomycin glycopeptide. bGtfA transferred 4-epi-vancosamine to vancomycin pseudoaglycone to make an analog of balhimycin. These results establish enzymatic activity of these five glycosyltransferases.

ISBN: 0493975772Subjects--Topical Terms:

226900
Chemistry, Biochemistry.

Glycosyltransferases involved in the biosynthesis of glycopeptide antibiotics.
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500 $a Source: Dissertation Abstracts International, Volume: 64-01, Section: B, page: 0190.
502 $a Thesis (Ph.D.)--Harvard University, 2003.
520 $a Glycosyltransferase genes were cloned from glycopeptide-producing strains of chloroeremomycin (GtfA, GtfB, GtfC), vancomycin (GtfD, GtfE), and balhimycin (bGtfA). The purified glycosyltransferases were then characterized for activity. GtfB and GtfE transferred glucose from UDP-glucose to the natural acceptor substrate, vancomycin aglycone, and GtfE also recognized the teicoplanin aglycone. GtfC and GtfD transferred 4-epi-vancosamine from UDP-4- epi-vancosamine to the vancomycin pseudoaglycone making epivancomycin. In tandem, GtfE and GtfD synthesized a novel hybrid teicoplanin/vancomycin glycopeptide. bGtfA transferred 4-epi-vancosamine to vancomycin pseudoaglycone to make an analog of balhimycin. These results establish enzymatic activity of these five glycosyltransferases.
520 $a Taken together, the above results demonstrate that the glycopeptide glycosyltransferases will be useful for making many derivatives of glycopeptide antibiotics with altered glycosylation patterns.
520 $a The glycopeptides vancomycin and teicoplanin are clinically important antibiotics for treating infections caused by Gram-positive pathogens. The rise in vancomycin resistance has created an urgent need for compounds active against resistant bacterial strains. The carbohydrate portions of these molecules affect biological activity, and there is great interest in developing efficient strategies to make carbohydrate derivatives.
520 $a Understanding the requirements for recognition and catalysis of glycopeptide glycosyltransferases is crucial for combinatorial biosynthesis. The X-ray crystal structure of the glucosyltransferase GtfB has been determined at 1.8 A. GtfB has a two domain structure with a deep interdomain cleft that is the probable binding site for UDP-glucose. A hydrophobic patch on the surface of the N-terminal domain is proposed to bind the aglycone substrate. Identified through mutagenesis, Asp332 is the best candidate for the general base in the glucosyltransfer reaction. Two structures of GtfA at 3.0 A have also been determined either in complex with vancomycin or UDP, demonstrating that our predictions for substrate binding are correct.
520 $a We generated a library of NDP-glucose derivatives to test the substrate flexibility of GtfE. All four regioisomers of TDP-deoxyglucose and NDP-aminoglucose were recognized and transferred by GtfE to both the vancomycin and teicoplanin scaffolds. Subsequent elaboration with 4-epi-vancosamine by GtfD generated vancomycin and teicoplanin derivatives with variant disaccharides. After transfer of 2-amino-glucose to teicoplanin and vancomycin aglycones by GtfE, N-acylation yielded analogs of vancomycin and teicoplanin active against VanB-type vancomycin-resistant enterococci.
590 $a School code: 0084.
650 $a Chemistry, Biochemistry. $3 226900
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