Terpene Biosynthesis Mechanisms and Enzyme Dynamics

Terpenes constitute the largest and most structurally diverse class of natural products, assembled from five-carbon units through a cascade of enzymatic reactions. The pathway begins with the formation of isopentenyl diphosphate (IPP) and its isomer dimethylallyl diphosphate (DMAPP) via the mevalonate or methylerythritol phosphate routes. Prenyltransferases then catalyse head-to-tail condensations to yield linear precursors such as geranyl, farnesyl and geranylgeranyl diphosphates. Terpene synthases orchestrate the conversion of these polyprenyl substrates into complex cyclic frameworks by stabilising transient carbocation intermediates and guiding selective cyclisation, rearrangement and termination steps. Recent advances in structural biology and computational simulation have begun to unravel the conformational dynamics and active-site microenvironments that underpin product specificity and catalytic promiscuity. An improved mechanistic understanding is driving the rational engineering of terpene synthases for the sustainable biosynthesis of high-value compounds in pharmaceuticals, agriculture and materials science.

Research from Nature Portfolio

High-resolution crystal structures of a bacterial diterpene synthase in both apo and substrate-bound forms have revealed how atypical active-site motifs compensate for the absence of canonical aspartate residues. Multiscale molecular dynamics and targeted mutagenesis uncovered the determinants of substrate promiscuity and enabled semi-rational engineering of the enzyme to accept larger prenyl diphosphates, thereby expanding its product repertoire. In parallel, the discovery of two fungal triterpene synthases operating independently of squalene has redefined triterpene biosynthesis. Isotopic labelling experiments and structural analyses elucidated novel cyclisation pathways from dimethylallyl and isopentenyl diphosphates, while an AlphaFold-driven mining strategy identified further non-canonical triterpene synthases. These studies collectively illuminate new enzymatic paradigms for generating high-carbon terpenes without reliance on traditional polyisoprenyl substrates.

Terpene Biosynthesis Mechanisms and Enzyme Dynamics publication trend

The graph below shows the total number of articles in terpene biosynthesis mechanisms and enzyme dynamics across all publications each year (not limited to Nature Index journals).

Technical terms

Isopentenyl diphosphate (IPP): Five-carbon building block for all terpenes.

Dimethylallyl diphosphate (DMAPP): Isomer of IPP that serves as the electrophilic partner in prenyl condensations.

Prenyltransferase: Enzyme that joins IPP and DMAPP units to form linear polyprenyl diphosphates.

Terpene synthase: Enzyme that catalyses cyclisation and rearrangement of linear precursors into cyclic terpenes via carbocation intermediates.

Carbocation intermediate: Positively charged carbon species central to cyclisation and rearrangement chemistry.

Catalytic promiscuity: Ability of an enzyme to accept multiple substrates or produce diverse products.

References

1. Molecular insights into the catalytic promiscuity of a bacterial diterpene synthase. Nature Communications (2023).
2. Discovery of non-squalene triterpenes. Nature (2022).
3. Decoding Catalysis by Terpene Synthases. ACS Catalysis (2023).
4. From Monocyclization to Pentacyclization: A Versatile Plant Cyclase Produces Diverse Sesterterpenes with Anti‐Liver Fibrosis Potential. Advanced Science (2025).