Terpene cyclases

IPP and DMAPP lead to geranylpyrophosphate (GPP), which is an immediate precursor of monoterpenes. The formation of nerylpyrophosphate (NPP) from GPP gives rise to a wide range of acyclic, cyclic, bicyclic or tricyclic skeletons. Reactions like rearrangement, oxidation, reduction and hydration via various terpene cyclases result in the formation of numerous terpene derivatives. Condensation of GPP and IPP leads to farnesylpyrophosphate (FPP), the immediate precursor of sesquiterpenoids. Likewise, FPP and IPP are conducive to diterpenoids. 

Terpenoids are synthesised by the condensation of a series of isoprene (2-meth-ylbuta-1,3-diene) units, followed by enzymatic cyclisation by a terpene cyclase, and subsequent modification such as hydroxylation, and are grouped on the basis of their carbon chain length. Monoterpenes and sesquiterpenes consisting of ten and 15 carbon atoms, respectively, are ranked among the most important aroma compounds. Despite their diversity, all terpenoids are synthesised... 

BACK, K. W., CHAPPELL, J., Identifying functional domains within terpene cyclases using a domain-swapping strategy, Proc. Neal. Acad. Sci. USA, 1996, 93, 6841-6845. 

Terpene synthases, also known as terpene cyclases because most of their products are cyclic, utilize a carbocationic reaction mechanism very similar to that employed by the prenyltransferases. Numerous experiments with inhibitors, substrate analogues and chemical model systems (Croteau, 1987 Cane, 1990, 1998) have revealed that the reaction usually begins with the divalent metal ion-assisted cleavage of the diphosphate moiety (Fig. 5.6). The resulting allylic carbocation may then cyclize by addition of the resonance-stabilized cationic centre to one of the other carbon-carbon double bonds in the substrate. The cyclization is followed by a series of rearrangements that may include hydride shifts, alkyl shifts, deprotonation, reprotonation and additional cyclizations, all mediated through enzyme-bound carbocationic intermed iates. The reaction cascade terminates by deprotonation of the cation to an olefin or capture by a nucleophile, such as water. Since the native substrates of terpene synthases are all configured with trans (E) double bonds, they are unable to cyclize directly to many of the carbon skeletons found in nature. In such cases, the cyclization process is preceded by isomerization of the initial carbocation to an intermediate capable of cyclization. 

Back, K. and Chappell, J. (1995) Cloning and bacterial expression of a sesquiterpene cyclase from Hyoscyamus muticus and its molecular comparison to related terpene cyclases. /. Biol. Chem., 270, 7375-81. 

Paschall CM, Hasserodt J, Jones T, Lemer RA, Janda KD, Christianson DW. Convergence of catalytic antibody and terpene cyclase mechanisms polyene cyclization directed by carbocation-p interactions. Angew. Chem. Int. Ed. Engl. 1999 38(12) 1743-1747. 

Terpene cyclase enzymes catalyze the cychzation of allylic pyrophosphate substrates to form carbocyclic products via car-bocation reaction intermediates. One well-studied example is pentalenene synthase (11, 12), which catalyzes the cychzation of farnesyl pyrophosphate to give pentalenene, whose reaction mechanism is shown in Fig. 15. Cychzation of farnesyl pyrophosphate is proposed to form an 11-membered intermediate, humulene, which is followed by a five-membered ring closure to form a bicychc tertiary carbocation. 1,2-Hydride migration followed by an additional five-membered ring closure gives a tricyclic carbocation, which gives pentalenene, at elimination. 

For instance, terpene cyclases are known to catalyze the conversion of oligomeric isoprenoid pyrophosphate substrates to polycyclic hydrocarbon products. Sequence comparisons of terpene cyclases with different known specificity can allow them to be classified into monoterpene, sesquiterpene, and diterpene synthases, which utilize the 10-carbon substrate geranyl pyrophosphate, the 15-carbon substrate famesyl pyrophosphate, and the 20-carbon substrate geranyl-geranyl pyrophosphate, respectively, on the basis of sequence criteria. 

Foo K, Usui I, Gotz DCG, Werner EW, Holte D, Baran PS (2012) Scalable, enantioselective synthesis of gcmnacrenes and related sesquiterpenes inspired by terpene cyclase phase logic. Angew Chem Int Ed 51 11491-11495... 

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