New N-acetyltransferase fold in the structure and mechanism of the phosphonate biosynthetic enzyme FrbF

Brian Bae, Ryan E. Cobb, Matthew A. DeSieno, Huimin Zhao, Satish K. Nair

Research output: Contribution to journalArticle

Abstract

The enzyme FrbF from Streptomyces rubellomurinus has attracted significant attention due to its role in the biosynthesis of the antimalarial phosphonate FR-900098. The enzyme catalyzes acetyl transfer onto the hydroxamate of the FR-900098 precursors cytidine 5′-monophosphate-3-aminopropylphosphonate and cytidine 5′-monophosphate-N-hydroxy-3-aminopropylphosphonate. Despite the established function as a bona fide N-acetyltransferase, FrbF shows no sequence similarity to any member of the GCN5-like N-acetyltransferase (GNAT) superfamily. Here, we present the 2.0 Å resolution crystal structure of FrbF in complex with acetyl-CoA, which demonstrates a unique architecture that is distinct from those of canonical GNAT-like acetyltransferases. We also utilized the co-crystal structure to guide structure-function studies that identified the roles of putative active site residues in the acetyltransferase mechanism. The combined biochemical and structural analyses of FrbF provide insights into this previously uncharacterized family of N-acetyltransferases and also provide a molecular framework toward the production of novel N-acyl derivatives of FR-900098.

Original languageEnglish (US)
Pages (from-to)36132-36141
Number of pages10
JournalJournal of Biological Chemistry
Volume286
Issue number41
DOIs
StatePublished - Oct 14 2011

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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