Manipulation of prenylation reactions by structure-based engineering of bacterial indolactam prenyltransferases

Takahiro Mori, Lihan Zhang, Takayoshi Awakawa, Shotaro Hoshino, Masahiro Okada, Hiroyuki Morita () and Ikuro Abe ()
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Takahiro Mori: Graduate School of Pharmaceutical Sciences, The University of Tokyo
Lihan Zhang: Graduate School of Pharmaceutical Sciences, The University of Tokyo
Takayoshi Awakawa: Graduate School of Pharmaceutical Sciences, The University of Tokyo
Shotaro Hoshino: Graduate School of Pharmaceutical Sciences, The University of Tokyo
Masahiro Okada: Graduate School of Pharmaceutical Sciences, The University of Tokyo
Hiroyuki Morita: Institute of Natural Medicine, University of Toyama
Ikuro Abe: Graduate School of Pharmaceutical Sciences, The University of Tokyo

Nature Communications, 2016, vol. 7, issue 1, 1-11

Abstract: Abstract Prenylation reactions play crucial roles in controlling the activities of biomolecules. Bacterial prenyltransferases, TleC from Streptomyces blastmyceticus and MpnD from Marinactinospora thermotolerans, catalyse the ‘reverse’ prenylation of (−)-indolactam V at the C-7 position of the indole ring with geranyl pyrophosphate or dimethylallyl pyrophosphate, to produce lyngbyatoxin or pendolmycin, respectively. Using in vitro analyses, here we show that both TleC and MpnD exhibit relaxed substrate specificities and accept various chain lengths (C5–C25) of the prenyl donors. Comparisons of the crystal structures and their ternary complexes with (−)-indolactam V and dimethylallyl S-thiophosphate revealed the intimate structural details of the enzyme-catalysed ‘reverse’ prenylation reactions and identified the active-site residues governing the selection of the substrates. Furthermore, structure-based enzyme engineering successfully altered the preference for the prenyl chain length of the substrates, as well as the regio- and stereo-selectivities of the prenylation reactions, to produce a series of unnatural novel indolactams.

Date: 2016
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DOI: 10.1038/ncomms10849

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