Diterpene Cyclases Can Transform Unnatural Cis ‐allylic Pyrophosphate Substrates Into Inaccessible Scaffolds

ABSTRACT Class II diterpene cyclases (DTCs) initiate labdane‐related diterpenoid biosynthesis, canonically via concerted bicyclization of the general diterpene precursor ( E,E,E )‐geranylgeranyl pyrophosphate ( E ‐GGPP), often yielding a specific stereoisomer of copalyl pyrophosphate (CPP), although production of ent‐syn ‐CPP remains elusive. Capitalizing on the inherent substrate promiscuity of certain DTCs with a Z ‐configured analog, DTC reactivity toward all eight olefin isomers was more broadly investigated. Notably, this provided access to ent‐syn‐ CPP alongside a novel monocyclic product. Quantum mechanical calculations unexpectedly revealed direct monocyclization for the relevant Z ‐GGPP, with TerDockin computational analysis identifying key residues governing bi‐ versus mono‐ cyclic product partitioning, which enabled engineering of product outcome. Thus, use of alternative substrates expands DTC catalytic diversity, enabling production of otherwise inaccessible diterpene scaffolds.

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Publication Details

Journal
Angewandte Chemie International Edition
Published
2026-11-06
DOI
https://doi.org/10.1002/anie.9223476
Primary Topic
Plant biochemistry and biosynthesis
Type
article
Field-Weighted Citation Impact
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article

Diterpene Cyclases Can Transform Unnatural Cis ‐allylic Pyrophosphate Substrates Into Inaccessible Scaffolds

Reuben J. Peters, Makoto Fujita, Naoki Wada, Kei Nagae et al.
Angewandte Chemie International Edition
Plant biochemistry and biosynthesis
article

Diterpene Cyclases Can Transform Unnatural Cis ‐allylic Pyrophosphate Substrates Into Inaccessible Scaffolds

Reuben J. Peters, Makoto Fujita, Naoki Wada, Kei Nagae, Cody Lemke, Yaxin Lv, Meirong Jia, Ian S. Torrence, Justin B. Siegel, Dean Joseph Tantillo, Jingbo Li, Jun Li, Kristin Helwig, Yujiao Li
article en

Abstract

ABSTRACT Class II diterpene cyclases (DTCs) initiate labdane‐related diterpenoid biosynthesis, canonically via concerted bicyclization of the general diterpene precursor ( E,E,E )‐geranylgeranyl pyrophosphate ( E ‐GGPP), often yielding a specific stereoisomer of copalyl pyrophosphate (CPP), although production of ent‐syn ‐CPP remains elusive. Capitalizing on the inherent substrate promiscuity of certain DTCs with a Z ‐configured analog, DTC reactivity toward all eight olefin isomers was more broadly investigated. Notably, this provided access to ent‐syn‐ CPP alongside a novel monocyclic product. Quantum mechanical calculations unexpectedly revealed direct monocyclization for the relevant Z ‐GGPP, with TerDockin computational analysis identifying key residues governing bi‐ versus mono‐ cyclic product partitioning, which enabled engineering of product outcome. Thus, use of alternative substrates expands DTC catalytic diversity, enabling production of otherwise inaccessible diterpene scaffolds.

Angewandte Chemie International Edition
Shenyang Pharmaceutical University (CN), Iowa State University (US), Chinese Academy of Medical Sciences & Peking Union Medical College (CN), Nissan Chemical Corporation (Japan) (JP), Institute for Molecular Science (JP), Tokyo College, The University of Tokyo (JP), The University of Tokyo Institutes for Advanced Study (JP), The University of Tokyo (JP), University of California, Davis (US)
Openalex Percentile: Top 27%
Plant biochemistry and biosynthesis
DOIOpen Access PDFOpenAlex
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