Incorporation of glucose analogs by GtfE and GtfD from the vancomycin biosynthetic pathway to generate variant glycopeptides

Heather C. Losey, Jiqing Jiang, John B. Biggins, Markus Oberthür, Xiang Yang Ye, Steven D. Dong, Daniel Kahne, Jon S. Thorson, Christopher T. Walsh

Research output: Contribution to journalArticlepeer-review

135 Scopus citations

Abstract

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 glycosyltransferases GtfE and GtfD. All four regioisomers (2-, 3-, 4-, 6-) of TDP-deoxyglucoses and UDP/TDP-aminoglucoses were prepared, predominantly by action of D-glucopyranosyl-1-phosphate thymidylyltransferase, Ep. 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 kcat and no effect on Km 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.

Original languageEnglish
Pages (from-to)1305-1314
Number of pages10
JournalChemistry and Biology
Volume9
Issue number12
DOIs
StatePublished - Dec 1 2002

Bibliographical note

Funding Information:
This work was supported by NIH grant 49338 to C.T.W.; NIH grants GM58196, CA84374, and AI52218 to J.S.T.; Alfred P. Sloan Fellowship to J.S.T.; PhRMA Foundation Fellowship to J.B.B.; and NIH grant 66174 to D.K. H.C.L. was a NSF graduate fellow.

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmacology
  • Drug Discovery
  • Clinical Biochemistry

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