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Biosynthesis of the enediyne antitumor antibiotic c-1027 involves a new branching point in chorismate metabolism

Academic Article
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Overview

authors

  • Van Lanen, S. G.
  • Lin, S. J.
  • Shen, Ben

publication date

  • January 2008

journal

  • Proceedings of the National Academy of Sciences of the United States of America  Journal

abstract

  • C-1027 is an enediyne antitumor antibiotic composed of four distinct moieties: an enediyne core, a deoxy aminosugar, a beta-amino acid, and a benzoxazolinate moiety. We now show that the benzoxazolinate moiety is derived from chorismate by the sequential action of two enzymes-SgcD, a 2-amino-2-deoxyisochorismate (ADIC) synthase and SgcG, an iron-sulfur, FMN-dependent ADIC dehydrogenase-to generate 3-enolpyruvoylanthranilate (OPA), a new intermediate in chorismate metabolism. The functional elucidation and catalytic properties of each enzyme are described, including spectroscopic characterization of the products and the development of a fluorescence-based assay for kinetic analysis. SgcD joins isochorismate (IC) synthase and 4-amino-4-deoxychorismate (ADC) synthase as anthranilate synthase component I (ASI) homologues that are devoid of pyruvate lyase activity inherent in ASI; yet, in contrast to IC and ADC synthase, SgcD has retained the ability to aminate chorismate identically to that observed for ASI. The net conversion of chorismate to OPA by the tandem action of SgcD and SgcG unambiguously establishes a new branching point in chorismate metabolism.

subject areas

  • Amino Acid Transport Systems
  • Aminoglycosides
  • Antineoplastic Agents
  • Antiporters
  • Binding Sites
  • Chorismic Acid
  • Choroiditis
  • Chromatography, High Pressure Liquid
  • Computational Biology
  • DNA
  • Enediynes
  • Escherichia coli Proteins
  • Kinetics
  • Models, Chemical
  • Neoplasms
  • Oxidoreductases Acting on CH-CH Group Donors
  • Streptomyces
  • Transaminases
  • ortho-Aminobenzoates
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Research

keywords

  • 2-amino-2-deoxyisochorismate dehydrogenase
  • 2-amino-2-deoxyisochorismate synthase
  • 3-enolpyruvoylanthranilate
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Identity

PubMed Central ID

  • PMC2206564

International Standard Serial Number (ISSN)

  • 0027-8424

Digital Object Identifier (DOI)

  • 10.1073/pnas.0708750105

PubMed ID

  • 18182490
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Additional Document Info

start page

  • 494

end page

  • 499

volume

  • 105

issue

  • 2

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