9MLO

Drimenol Synthase - Farnesyl Thiol Complex

これはPDB形式変換不可エントリーです。

9MLO の概要

• エントリーDOI: 10.2210/pdb9mlo/pdb
• 分子名称: Haloacid dehalogenase superfamily, subfamily IA, variant 3 with third motif having DD or ED, GLYCEROL, (2E,6E)-3,7,11-trimethyldodeca-2,6,10-triene-1-thiol, ... (6 entities in total)
• 機能のキーワード: terpene synthase, phosphatase, isoprenoid, lyase
• 由来する生物種: Aquimarina spongiae
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 122850.58

構造登録者

Osika, K.R.,Gaynes, M.N.,Christianson, D.W. (登録日: 2024-12-19, 公開日: 2025-07-16)

主引用文献

Osika, K.R.,Gaynes, M.N.,Christianson, D.W.
Crystal structure and catalytic mechanism of drimenol synthase, an unusual bifunctional terpene cyclase-phosphatase.
Proc.Natl.Acad.Sci.USA, 122:e2506584122-e2506584122, 2025

PubMed Abstract: Drimenol synthase from (AsDMS) is a highly unusual chimera 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. The AsDMS structure exhibits a didomain architecture consisting of a terpene cyclase β domain and a haloacid dehalogenase-like phosphatase domain, with two distinct active sites located on opposite sides of the protein. Mechanistic studies show that dephosphorylation of the drimenyl diphosphate intermediate proceeds through stepwise hydrolysis such that two equivalents of inorganic phosphate rather than inorganic pyrophosphate are coproducts of the reaction sequence. When the AsDMS reaction is performed in HO, O is not incorporated into drimenol, indicating that the hydroxyl oxygen of drimenol originates from the prenyl oxygen of FPP rather than a water molecule from bulk solution. These results correct a mechanistic proposal previously advanced by another group. Surprisingly, AsDMS exhibits substrate promiscuity, catalyzing the conversion of the slowly reactive substrate mimic farnesyl--thiolodiphosphate into cyclic and linear sesquiterpene products. Structural and mechanistic insights gained from AsDMS illustrate the functional diversity of terpene biosynthetic enzymes and provide a foundation for engineering "designer cyclase" assemblies capable of generating a wide variety of terpenoid products.

PubMed: 40569382
DOI: 10.1073/pnas.2506584122

実験手法

X-RAY DIFFRACTION (2.64 Å)