Biocatalytic Ether Lipid Synthesis by an Archaeal Glycerolprenylase

14 February 2024, Version 1
This content is a preprint and has not undergone peer review at the time of posting.

Abstract

Although ethers are common in secondary natural products, they are an underrepresented functional group in primary metabolism. As such, there are comparably few enzymes capable of constructing ether bonds in a general fashion. However, such enzymes are highly sought after for synthetic applications as they typically operate with higher regioselectivity and under milder conditions than traditional organochemical approaches. To expand the repertoire of well characterized ether synthases, we herein report on a promiscuous archaeal prenyltransferase from the scarcely researched family of geranylgeranylglyceryl phosphate synthases (GGGPSs or G3PSs). We show that the ultrastable Archaeoglobus fulgidus G3PS makes various (E)- and (Z)-configured prenyl glycerol ethers from the corresponding pyrophosphates, while exerting perfect control over the configuration at the glycerol unit. Based on experimental and computational data, we propose a mechanism for this enzyme which involves an intermediary prenyl carbocation equivalent. As such, this study provides the fundamental understanding and methods to introduce G3PSs into the biocatalytic alkylation toolbox.

Keywords

enzyme
pyrophosphate
kinetics
assay
spectroscopy
crystallography
mechanisms

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Supplementary information containing author contributions, data availability and accessibility statements, additional summary and discussion of relevant literature, experimental details, additional biochemical data, synthetic procedures and analytical data, crystallographic data, and computational details.
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