22ua | pdb_000022ua
Crystal structure of AstC terpene cyclase domain in complex with albicanoyl monophosphate
Structural highlights
Publication Abstract from PubMedDrimane-type sesquiterpenes (DTSs) are a widely distributed terpenoid family with diverse and potent bioactivities. Although DTS synthases occur in plants, bacteria, and fungi, they share little sequence identity across kingdoms, obscuring the mechanistic principles that govern drimane scaffold formation and product phosphorylation states. Haloacid dehalogenase (HAD)-like terpene cyclases (TCs), TC domains fused to HAD-like phosphatases, are especially intriguing because they couple cyclization with dephosphorylation, yet how these enzymes control scaffold outcomes and phosphorylation states across kingdoms remains unresolved. Here, we identify the fungal enzyme AacA as a bifunctional albicanoyl monophosphate synthase that catalyzes class II cyclization of farnesyl pyrophosphate, followed by Mg(2+)-dependent dephosphorylation. We further determine the X-ray crystal structures of the fungal drim-8-ene-11-yl pyrophosphate synthase AstC, representing the first structures of fungal HAD-like terpene cyclases. These structures capture substrate- and product-mimic states and reveal a head-to-tail homodimer in which the partner HAD-like domain caps the TC active site and positions the pyrophosphate at the intersubunit interface, consistent with trans-domain intermediate transfer. In addition, phosphate-release kinetics support cross-monomer TC-to-HAD coupling in dimeric AacA. Structure-guided mutagenesis and assays with farnesyl mono- and thiopyrophosphate analogues further define the determinants of product selectivity and the distinct dephosphorylation capacities of these enzymes. These findings expand fungal DTS enzymology and guide TC engineering. Dimerization-Dependent Trans-Domain Coupling Enables Intermediate Transfer in Fungal Haloacid Dehalogenase-Like Terpene Cyclases.,Chen TH, Huang KF, Chou TH, Tseng CC, Huang RJ, Ko TP, Liang SY, Chein RJ, Lin HC J Am Chem Soc. 2026 Jun 3;148(21):22120-22130. doi: 10.1021/jacs.6c04151. Epub , 2026 May 15. PMID:42139319[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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