A novel 4-methylideneimidazole-5-one-containing tyrosine aminomutase in enediyne antitumor antibiotic C-1027 biosynthesis

J Am Chem Soc. 2003 May 21;125(20):6062-3. doi: 10.1021/ja034609m.

Abstract

The C-1027 enediyne antibiotic contains an unusual 3-chloro-4,5-dihydroxy-beta-phenylalanine moiety that is thought to be derived from tyrosine by an aminomutase reaction. However, none of the genes identified within the C-1027 gene cluster encode proteins with strong homology to known aminomutases. The sgcC4 gene encodes a protein with strong homology to dehydroalanine-dependent histidine/phenylalanine ammonia lyases. The sgcC4 gene was expressed in E. coli, and overproduced SgcC4 was purified as a His6-tagged fusion protein. Biochemical characterization of the purified SgcC4 establishes that SgcC4 is an aminomutase that catalyzes the conversion of l-tyrosine to (S)-beta-tyrosine and employs 4-methylideneimidazole-5-one (MIO) at its active site. The latter was supported by borohydride and cyanide inhibition studies and confirmed by site-directed mutagenesis. The S153A mutant exhibited a 340-fold decrease in kcat/KM. SgcC4 represents a novel type of aminomutase, extending the known MIO chemistry from ammonia lyases into aminomutases.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Alanine / analogs & derivatives*
  • Alanine / metabolism
  • Aminoglycosides*
  • Anti-Bacterial Agents / biosynthesis*
  • Antibiotics, Antineoplastic / biosynthesis*
  • Binding Sites
  • Chromatography, High Pressure Liquid
  • Enediynes
  • Imidazoles / metabolism*
  • Intramolecular Transferases / genetics
  • Intramolecular Transferases / metabolism*
  • Streptomyces / enzymology
  • Streptomyces / genetics
  • Streptomyces / metabolism

Substances

  • Aminoglycosides
  • Anti-Bacterial Agents
  • Antibiotics, Antineoplastic
  • Enediynes
  • Imidazoles
  • methylidene-imidazolone
  • C 1027
  • dehydroalanine
  • Intramolecular Transferases
  • tyrosine 2,3-aminomutase
  • Alanine