biostudies-literatureUnknownOsika KRNIGMS NIH HHSDrimenol synthase from <i>Aquimarina spongiae</i> (AsDMS) is a highly unusual bifunctional sesquiterpene synthase that integrates two distinct, sequential isoprenoid processing activities within a single polypeptide chain. AsDMS catalyzes the class II cyclization of farnesyl diphosphate (FPP) to form drimenyl diphosphate, which then undergoes enzyme-catalyzed hydrolysis to yield drimenol, a bioactive sesquiterpene alcohol with antifungal and anticancer properties. Here, we report the X-ray crystal structures of AsDMS and its complex with a sesquiterpene thiol, which are the first of a terpene cyclase-phosphatase. The AsDMS structure exhibits a two-domain architecture consisting of a terpene cyclase β domain and a haloacid dehalogenase (HAD)-like phosphatase domain, with two distinct activebioRxiv : the preprint server for biology2025.02.11.637696https://www.ebi.ac.uk/biostudies/studies/S-EPMC11844523biostudies-literatureCrystal Structure and Catalytic Mechanism of Drimenol Synthase, a Bifunctional Terpene Cyclase-Phosphatase.PMC11844523T32 GM133398P30 GM133893R01 GM056838Gaynes MNChristianson DWOsika KRfalseCrystal Structure and Catalytic Mechanism of Drimenol Synthase, a Bifunctional Terpene Cyclase-Phosphatase.Drimenol synthase from <i>Aquimarina spongiae</i> (AsDMS) is a highly unusual bifunctional sesquiterpene synthase that integrates two distinct, sequential isoprenoid processing activities within a single polypeptide chain. AsDMS catalyzes the class II cyclization of farnesyl diphosphate (FPP) to form drimenyl diphosphate, which then undergoes enzyme-catalyzed hydrolysis to yield drimenol, a bioactive sesquiterpene alcohol with antifungal and anticancer properties. Here, we report the X-ray crystal structures of AsDMS and its complex with a sesquiterpene thiol, which are the first of a terpene cyclase-phosphatase. The AsDMS structure exhibits a two-domain architecture consisting of a terpene cyclase β domain and a haloacid dehalogenase (HAD)-like phosphatase domain, with two distinct active2025-01-01T00:00:00Z2025 Feb2026-05-21T03:09:45.305Z2025-04-04T00:17:05.959ZS-EPMC118445233999049410.1101/2025.02.11.637696