Substrate Folding Modes in Trichodiene Synthase: A Determinant of Chemo- and Stereoselectivity

Abstract

The folding mode of substrate FPP in sesquiterpene cyclases/synthases is key to the chemo- and stereoselectivity of the ultimate sesquiterpene products. However, the precise substrate folding modes in most sesquiterpene cyclases are still elusive, and it is challenging for theoretical simulations due to the high flexibility of FPP. Herein, by DFT/MM MD simulations, we obtain the optimal folding mode of FPP in the 1,6-closure trichodiene synthase and illuminate the whole catalytic mechanism for the biosynthesis of trichodiene. Furthermore, a simple and practical rule is proposed to decipher the relationship between the diverse FPP folding modes and chemical selectivity toward 1,6- and 1,10-ring closure, which are common pathways in all sesquiterpene cyclases.

Comment on “Substrate Folding Modes in Trichodiene Synthase: A Determinant of Chemo- and Stereoselectivity”

“…2a in Ref. 1 ), and indeed, was a main result of their work. Wang et al utilized this conformation for FPP in their mechanistic studies.…”

“…S7 in Ref. 1). In contrast, it is, in fact, the C12-methyl group (standard numbering), trans to C9 of FPP, that migrates.…”

“…Note that the numbering for the C12/C13 atoms is inverted in Ref. 1 , but to leave no room for misunderstanding, C12 in Ref. 1 is the methyl group “cis” to C9 of FPP, whereas the standard IUPAC style numbering for the cis carbon is C13 used in our and other publications.…”

“…1 , but to leave no room for misunderstanding, C12 in Ref. 1 is the methyl group “cis” to C9 of FPP, whereas the standard IUPAC style numbering for the cis carbon is C13 used in our and other publications. 5 The correctly folded conformation used in our earlier work is shown schematically in Scheme 3a, whereas the incorrectly folded conformation used by Wang et al is shown in Scheme 3b.…”

“…1 In that work, the authors followed essentially the same procedures, including exactly the same level of theory described in Ref. 2 , but started by docking the large, open structure of FPP directly into the active site.…”