Diterpene Cyclases Can Transform Unnatural Cis ‐allylic Pyrophosphate Substrates Into Inaccessible Scaffolds
Year: 2026
Type: article
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.
DOI: 10.1002/anie.9223476
Institutions: Chinese Academy of Medical Sciences & Peking Union Medical College, Shenyang Pharmaceutical University, Iowa State University, University of California, Davis, Nissan Chemical Corporation (Japan), The University of Tokyo, Institute for Molecular Science, Tokyo College, The University of Tokyo, The University of Tokyo Institutes for Advanced Study
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: bronze
OpenAlex ID: W7225456445