Multi-domain terpenoid cyclase architecture and prospects for proximity in bifunctional catalysis

[Display omitted] •Terpenoid cyclases catalyze complex carbon–carbon bond forming reactions in biology.•Terpenoid cyclases consist of three basic domain types designated α, β, and γ⋅⋅⋅⋅⋅•Class I cyclases utilize the α domain, and class II cyclases utilize the βγ domains.•Bifunctional terpenoid cyclases adopt αα and αβγ domain architectures.•Multi-domain architectures may enable proximity or cluster channeling in catalysis. Crystal structures of terpenoid cyclases reveal assemblies of three basic domains designated α, β, and γ. While the biosynthesis of cyclic monoterpenes (C10) and sesquiterpenes (C15) most often involves enzymes with α or αβ domain architecture, the biosynthesis of cyclic diterpenes (C20), sesterterpenes (C25), and triterpenes (C30) can involve enzymes with α, αα, βγ, or αβγ domain architecture. Indeed, some enzymes of terpenoid biosynthesis are bifunctional, with distinct active sites that catalyze sequential reactions. Interestingly, some of these enzymes oligomerize to form dimers, tetramers, and hexamers. Not only can such assemblies enable enzyme regulation by allostery, but they can also provide a modest enhancement of terpenoid product flux through proximity channeling or cluster channeling. The mixing and matching of functional terpenoid cyclase domains through tertiary and/or quaternary structure may also comprise an evolutionary strategy for facile product diversification.