Abstract
We report the first X-ray crystallographic structure of the “head-to-middle” prenyltransferase, isosesquilavandulyl diphosphate synthase, involved in biosynthesis of the merochlorin class of antibiotics. The protein adopts the ζ or cis-prenyl transferase fold but remarkably, unlike tuberculosinol adenosine synthase and other cis-prenyl transferases (e.g. cis-farnesyl, decaprenyl, undecaprenyl diphosphate synthases), the large, hydrophobic side chain does not occupy a central hydrophobic tunnel. Instead, it occupies a surface pocket oriented at 90° to the hydrophobic tunnel. Product chain-length control is achieved by squeezing out the ligand from the conventional allylic S1 binding site, with proton abstraction being achieved using a diphosphate-Asn-Ser relay. The structures revise and unify our thinking as to the mechanism of action of many other prenyl transferases and may also be of use in engineering new merochlorin-class antibiotics.
Original language | English (US) |
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Pages (from-to) | 683-687 |
Number of pages | 5 |
Journal | Angewandte Chemie - International Edition |
Volume | 57 |
Issue number | 3 |
DOIs | |
State | Published - Jan 15 2018 |
Keywords
- X-ray diffraction
- antibiotics
- enzymes
- isoprenoids
- protein structures
ASJC Scopus subject areas
- Catalysis
- General Chemistry