Generation of new landomycins by combinatorial biosynthetic manipulation of the LndGT4 gene of the landomycin E cluster in S. globisporus

Bohdan Ostash, Uwe Rix, Lily L.Remsing Rix, Tao Liu, Felipe Lombo, Andriy Luzhetskyy, Oleksandr Gromyko, Chenchen Wang, Alfredo F. Braña, Carmen Méndez, José A. Salas, Victor Fedorenko, Jürgen Rohr

Research output: Contribution to journalArticlepeer-review

67 Scopus citations

Abstract

A 3 kb DNA fragment from the Streptomyces globisporus 1912 landomycin E (LaE) biosynthetic gene cluster (lnd) was completely sequenced. Three open reading frames were identified, lndGT4, lndZ4, and lndZ5, whose probable translation products resemble a glycosyltransferase, a reductase, and a hydroxylase, respectively. Studies of generated mutants from disruption and complementation experiments involving the lndGT4 gene allowed us to determine that LndGT4 controls the terminal L-rhodinose sugar attachment during LaE biosynthesis and that LndZ4/LndZ5 are responsible for the unique C11-hydroxylation of the landomycins. Generation of the novel landomycins F, G, and H in the course of these studies provided evidence for the flexibility of lnd glycosyltransferases toward their acceptor substrates and a basis for initial structure-activity relationships within the landomycin family of antibiotics.

Original languageEnglish
Pages (from-to)547-555
Number of pages9
JournalChemistry and Biology
Volume11
Issue number4
DOIs
StatePublished - Apr 2004

Bibliographical note

Funding Information:
This work was supported by NIH grant RO1-CA091901 (to J.R.), INTAS grants YSF 00-208 (to B.O.) and YSF 00-186 (to A.L.), WUBMRC grant to B.O. and O.G., and grant Bg117b of the Ukrainian Ministry of Education and Science (to V.F.). Research at the Oviedo laboratory was financed by grants of the Spanish Ministry of Science and Technology (BMC2002-03599 to C.M.) and a grant of the Plan Regional de Investigación del Principado de Asturias (GE-MEDO1-05 to J.A.S.). We thank Dr. Val Adams, College of Pharmacy, University of Kentucky, for providing the facilities for testing the antitumor activities of Las and the Mass Spectrometry facility of the University of Kentucky for the high-resolution mass spectra.

ASJC Scopus subject areas

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

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