Distinct Structural Elements Dictate the Specificity of the Type III Pentaketide Synthase from Neurospora crassa

Sheryl B. Rubin-Pitel, Houjin Zhang, Trang Vu, Joseph S. Brunzelle, Huimin Zhao*, Satish K. Nair

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

28 Scopus citations

Abstract

The fungal type III polyketide synthase 2′-oxoalkylresorcylic acid synthase (ORAS) primes with a range of acyl-Coenzyme A thioesters (C4-C20) and extends using malonyl-Coenzyme A to produce pyrones, resorcinols, and resorcylic acids. To gain insight into this unusual substrate specificity and product profile, we have determined the crystal structures of ORAS to 1.75 Å resolution, the Phe-252→Gly site-directed mutant to 2.1 Å resolution, and a binary complex of ORAS with eicosanoic acid to 2.0 Å resolution. The structures reveal a distinct rearrangement of structural elements near the active site that allows accommodation of long-chain fatty acid esters and a reorientation of the gating mechanism that controls cyclization and polyketide chain length. The roles of these structural elements are further elucidated by characterization of various structure-based site-directed variants. These studies establish an unexpected plasticity to the PKS fold, unanticipated from structural studies of other members of this enzyme family.

Original languageEnglish (US)
Pages (from-to)1079-1090
Number of pages12
JournalChemistry and Biology
Volume15
Issue number10
DOIs
StatePublished - Oct 20 2008

Keywords

  • CHEMBIO

ASJC Scopus subject areas

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

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