22UA

Crystal structure of AstC terpene cyclase domain in complex with albicanoyl monophosphate

This is a non-PDB format compatible entry.

Summary for 22UA

• Entry DOI: 10.2210/pdb22ua/pdb
• Descriptor: AstC, GLYCEROL, [(1~{S},4~{a}~{S},8~{a}~{S})-5,5,8~{a}-trimethyl-2-methylidene-3,4,4~{a},6,7,8-hexahydro-1~{H}-naphthalen-1-yl]methyl dihydrogen phosphate, ... (4 entities in total)
• Functional Keywords: haloacid dehalogenase-like terpene cyclase, biosynthetic protein
• Biological source: Aspergillus oryzae
• Total number of polymer chains: 2
• Total formula weight: 69815.66

Authors

Chen, T.-H.,Huang, K.-F.,Ko, T.-P.,Lin, H.-C. (deposition date: 2026-01-23, release date: 2026-07-29)

Primary citation

Chen, T.H.,Huang, K.F.,Chou, T.H.,Tseng, C.C.,Huang, R.J.,Ko, T.P.,Liang, S.Y.,Chein, R.J.,Lin, H.C.
Dimerization-Dependent Trans-Domain Coupling Enables Intermediate Transfer in Fungal Haloacid Dehalogenase-Like Terpene Cyclases.
J.Am.Chem.Soc., 148:22120-22130, 2026

PubMed Abstract: Drimane-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-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 -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.

PubMed: 42139319
DOI: 10.1021/jacs.6c04151

Experimental method

X-RAY DIFFRACTION (2.86 Å)