Abstract

Drimane-type sesquiterpenoids (DMTs) are characterized by a distinctive 6/6 bicyclic skeleton comprising the A and B rings. While DMTs are commonly found in fungi and plants, their presence in bacteria has not been reported. Moreover, the biosynthetic pathways for DMTs have been primarily elucidated in fungi, with identified P450s only acting on the B ring. In this study, we isolated and characterized three bacterial DMTs, namely 3β-hydroxydrimenol (2), 2α-hydroxydrimenol (3), and 3-ketodrimenol (4), from Streptomyces clavuligerus. Through genome mining and heterologous expression, we identified a cav biosynthetic gene cluster responsible for the biosynthesis of DMTs 2–4, along with a P450, CavA, responsible for introducing the C-2 and C-3 hydroxy groups. Furthermore, the substrate scope of CavA revealed its ability to hydroxylate drimenol analogs. This discovery not only broadens the known chemical diversity of DMTs from bacteria, but also provides new insights into DMT biosynthesis in bacteria.

Beilstein J. Org. Chem. 2024, 20, 815–822. doi:10.3762/bjoc.20.73

摘要

Drimane 型倍半萜类化合物 (DMT) 的特点是具有独特的 6/6 双环骨架，包含 A 环和 B 环。虽然 DMT 常见于真菌和植物中，但其在细菌中的存在尚未有报道。此外，DMT 的生物合成途径已主要在真菌中阐明，已鉴定的 P450 仅作用于 B 环。在本研究中，我们从棒状链霉菌中分离并鉴定了三种细菌 DMT，即 3β-羟基补身醇 ( 2 )、2α-羟基补身醇 ( 3 ) 和 3-酮基补身醇 ( 4 ) 。通过基因组挖掘和异源表达，我们鉴定了负责DMT 2 – 4生物合成的cav生物合成基因簇，以及负责引入C-2和C-3羟基的P450 CavA。此外，CavA 的底物范围揭示了其羟基化补身醇类似物的能力。这一发现不仅拓宽了细菌中 DMT 的已知化学多样性，而且为细菌中 DMT 生物合成提供了新的见解。

贝尔斯坦 J. 组织。化学。 2024, 20, 815–822。 doi:10.3762/bjoc.20.73