A crystallographic investigation of phosphoantigen binding to isopentenyl pyrophosphate/dimethylallyl pyrophosphate isomerase

Johan Wouters, Fenglin Yin, Yongcheng Song, Yonghui Zhang, Yamina Oudjama, Victor Stalon, Louis Droogmans, Craig T. Morita, Eric Oldfield

Research output: Contribution to journalArticlepeer-review

Abstract

We report the crystallographic structures of the potent phosphoantigens Phosphostim (the bromohydrin of isopentenyl pyrophosphate) and E-4-hydroxy-3-methyl-but-2-enyl pyrophosphate bound to the mevalonate pathway enzyme isopentenyl pyrophosphate/dimethylallyl pyrophosphate isomerase (IPPI). Racemic Phosphostim forms covalent complexes with IPPI: a 4-thioether with C67 and a 4-ester with E116. Only the E116 ester forms with the chiral species, S-Phosphostim, with the w.t. enzyme, while the C67 thioether forms with a mutant Y104F IPPI. The potent phosphoantigen HMBPP also binds to IPPI, but is only a weak (50 μM) inhibitor. These results strongly support an SN2 reaction for inhibition of IPPI by Phosphostim, in contrast to the SN1 or concerted type of reaction found with epoxide inhibitors, which react at C-3, and are of general interest in the context of the development of novel mevalonate pathway inhibitors. They also provide clues as to the nature of the binding site of synthetic phosphoantigens in γδ T cell activation. In particular, both bromohydrin and epoxy phosphoantigens are potent, irreversible inhibitors of IPPI while HMBPP is only a weak inhibitor, ruling out an IPPI or IPPI-like target for HMBPP in γδ T cell activation.

Original languageEnglish (US)
Pages (from-to)536-537
Number of pages2
JournalJournal of the American Chemical Society
Volume127
Issue number2
DOIs
StatePublished - Jan 19 2005

ASJC Scopus subject areas

  • Catalysis
  • Chemistry(all)
  • Biochemistry
  • Colloid and Surface Chemistry

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