Mechanistic Similarities of Sesquiterpene Cyclases PenA, Omp6/7, and BcBOT2 Are Unraveled by an Unnatural “FPP-Ether” Derivative

Abstract

The sesquiterpene cyclases pentalenene synthase (PenA) and two Δ6-protoilludene synthases Omp6 and Omp7 convert a FPP ether into several new tetrahydrofurano terpenoids, one of which is also formed as the main product by the sesquiterpene cyclase BcBOT2. Thus, PenA, Omp6/7, and BcBOT2 follow closely related catalytic pathways and induce similar folding of their diphosphate substrates despite low levels of amino acid sequence similarity. Some of the new terpenoids show pronounced olfactoric properties.

New Trends and Future Opportunities in the Enzymatic Formation of C−C, C−N, and C−O bonds

“…[59] The cyclases used in their investigation were: patchoulol synthase (Pts) from Pogostemon cablin, viridiforene synthase (Tps32) from Solanum lycopersicum, vetispiradiene synthase (Hvs1) from Hyoscamus muticus, caryolan-1-ol synthase (GcoA1) from Streptomyces griseus, (+)-T-muurolol synthase (TmS) from Roseifexus castenholzii, pentalenene synthase (PenA) from Streptomyces exfoliatus, presilphiperfolan-8b-ol synthase (Bot2) from Botrytis cinerea, and cubebol synthase (Cop4) from Corinus cinereus. [60][61][62][63][64][65][66][67][68] The group initially found that the two amine-containing FPP derivatives were not converted by any of the enzymes. The cyclisation of the oxo-and thio-substrates was successfully achieved by a number of the STCs, generating a series of novel oxygen-and sulphur-containing macrocycles through a single CÀ C bond forming step.…”

“…who reported the synthesis of novel non‐natural terpenoids through the cyclisation of heteroatom‐modified FPPs with a number of STCs (Scheme 5). [59] The cyclases used in their investigation were: patchoulol synthase (Pts) from Pogostemon cablin , viridiforene synthase (Tps32) from Solanum lycopersicum , vetispiradiene synthase (Hvs1) from Hyoscamus muticus , caryolan‐1‐ol synthase (GcoA1) from Streptomyces griseus , (+)‐T‐muurolol synthase (TmS) from Roseifexus castenholzii , pentalenene synthase (PenA) from Streptomyces exfoliatus , presilphiperfolan‐8b‐ol synthase (Bot2) from Botrytis cinerea , and cubebol synthase (Cop4) from Corinus cinereus [60–68] . The group initially found that the two amine‐containing FPP derivatives were not converted by any of the enzymes.…”

Cyclopropylmethyldiphosphates are substrates for sesquiterpene synthases: experimental and theoretical results

“…In the case of BcBOT2, the product of such a cation cascade is the tricyclic sesquiterpene presilphiperfolan-8β-ol ( 2 ). 3 Interestingly, our recent studies 4 show that BcBOT2 is well suited to investigate the scope of substrate promiscuity of sesquiterpene cyclases (STCs). 5 In particular, we demonstrated that linear ether and thioether derivatives of FPP 1 , as well as isomers in which the methyl groups are shifted by one position on the alkenes toward the diphosphate group, are transformed by BcBOT2, leading to new unnatural sesquiterpene ring systems and backbones.…”

“…5 In particular, we demonstrated that linear ether and thioether derivatives of FPP 1 , as well as isomers in which the methyl groups are shifted by one position on the alkenes toward the diphosphate group, are transformed by BcBOT2, leading to new unnatural sesquiterpene ring systems and backbones. 4 The formation of 2 is initiated by a ring closure between carbon atoms 1 and 11.…”

Enzymatic Synthesis of Variediene Analogs

“…It is well known that prenyltransferases can use analogs of the terpene monomers dimethylallyl diphosphate (DMAPP) and isopentenyl diphosphate (IPP). [10] Recent research has demonstrated that TPSs convert various substrate analogs [11] including halogenated precursors,[ 12 , 13 , 14 , 15 ] hydroxylated oligoprenyl diphosphates,[ 16 , 17 ] epoxides, [18] ketones,[ 18 , 19 ] substrates with heteroatoms inserted into the chain,[ 20 , 21 ] with altered methylation pattern,[ 15 , 19 , 22 , 23 ] shifted[ 18 , 19 ] or saturated double bonds[ 18 , 24 , 25 ] into terpenoid compounds. This approach is conceptually highly interesting, because the required chemical synthesis of such (acyclic and achiral) substrate analogs is much easier than a stereoselective synthesis of the (poly)cyclic enzyme products.…”