Crystal structure of riboflavin synthase

Der Ing Liao*, Zdzislaw Wawrzak, Joseph C. Calabrese, Paul V. Viitanen, Douglas B. Jordan

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

56 Scopus citations

Abstract

Background: Riboflavin synthase catalyzes the dismutation of two molecules of 6,7-dimethyl-8-(1′-D-ribityl)-lumazine to yield riboflavin and 4-ribitylamino-5-amino-2,6-dihydroxypyrimidine. The homotrimer of 23 kDa subunits has no cofactor requirements for catalysis. The enzyme is nonexistent in humans and is an attractive target for antimicrobial agents of organisms whose pathogenicity depends on their ability to biosynthesize riboflavin. Results: The first three-dimensional structure of the enzyme was determined at 2.0 Å resolution using the multiwavelength anomalous diffraction (MAD) method on the Escherichia coli protein containing selenomethionine residues. The homotrimer consists of an asymmetric assembly of monomers, each of which comprises two similar β barrels and a C-terminal α helix. The similar β barrels within the monomer confirm a prediction of pseudo two-fold symmetry that is inferred from the sequence similarity between the two halves of the protein. The β barrels closely resemble folds found in phthalate dioxygenase reductase and other flavoproteins. Conclusions: The three active sites of the trimer are proposed to lie between pairs of monomers in which residues conserved among species reside, including two Asp-His-Ser triads and dyads of Cys-Ser and His-Thr. The proposed active sites are located where FMN (an analog of riboflavin) is modeled from an overlay of the β barrels of phthalate dioxygenase reductase and riboflavin synthase. In the trimer, one active site is formed, and the other two active sites are wide open and exposed to solvent. The nature of the trimer configuration suggests that only one active site can be formed and be catalytically competent at a time.

Original languageEnglish (US)
Article number99
Pages (from-to)399-408
Number of pages10
JournalStructure
Volume9
Issue number5
DOIs
StatePublished - 2001

Keywords

  • Antimicrobial target
  • Escherichia coli
  • Riboflavin biosynthesis
  • Riboflavin synthase
  • Structure-based design

ASJC Scopus subject areas

  • Structural Biology
  • Molecular Biology

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