Chimeric Terpene Synthases Possessing both Terpene Cyclization and Prenyltransfer Activities

Abstract

Prenyltransferase (PT) and terpene synthase (TPS) are key enzymes in the formation of the basic carbon skeletons of terpenoids. The PTs determine the prenyl carbon chain length, whereas TPSs generate the structural complexity of the molecular scaffolds, forming various ring structures. Normally, PTs and TPSs are separate, independent enzymes. However, in 2007, a chimeric enzyme, in which the PT was fused with the TPS, was found in a fungus. Recent studies have revealed that such chimeric TPSs are widely distributed in fungi and function in the biosyntheses of various terpene natural products, including sesterterpenes, which are a relatively rare group of terpenoids. This review summarizes the accumulated knowledge of these recently discovered, unique, chimeric TPSs.

A Family of Related Fungal and Bacterial Di‐ and Sesterterpenes: Studies on Fusaterpenol and Variediene

“…All these compounds have a cis ‐fused cyclopentane ring that arises biosynthetically from geranylgeranyl diphosphate (GGPP) or geranylfarnesyl diphosphate (GFPP) by an initial 1,11–10,14 cyclisation to the cationic intermediate A and a subsequent ring expansion with simultaneous ring contraction to the hypothetical secondary cation B that can stabilise by further 2,10 or 6,10 cyclisation (Scheme A). The known fungal representatives are generally made by bifunctional enzymes containing a terpene synthase domain and a prenyltransferase domain for GGPP or GFPP biosynthesis (TS+PT) and include phomopsene ( 1 ) and its derivative methyl phomopsenoate ( 2 ) from Phomopsis amygdali , variediene ( 3 ) from Emericella variecolor and the cyclopiane‐type diterpene ( 4 ) from Penicillium chrysogenum (Scheme B) . Compound 4 is the biosynthetic precursor of a group of oxidised derivatives such as conidiogenone ( 5 ), one of the first isolated compounds of this class that exhibits an interesting bioactivity as a potent inducer of conidiogenesis in Penicillium …”

Bacterial Diterpene Biosynthesis

“…Oxidation with ring contraction to GA 12 aldehyde (41) by CYP114 proceeds with specific extrusion of C-7, as demonstrated by a 13 C-labelling experiment through feeding with (2-13 C)mevalonolactone. [58] This step is followed by an oxidation to GA 12 (42)b yS DR GA .T he final oxidations to GA 15 (43), GA 24 (44), and GA 9 (45)a re performed by CYP112. [57] Notably,t he identified pathway intermediates and reactions are essentially the same as in plants and fungi, but the responsible enzymes are completely unrelated in all three cases,thus giving an interesting example of convergent evolution.…”

“…Thei ntricate mechanisms of bacterial enzymes associated with these cyclisation reactions and the accumulated knowledge on downstream modifications of diterpenes to bioactive molecules will be presented in this Minireview.D iterpene biosynthesis in plants and in fungi have recently been reviewed elsewhere. [10][11][12] This Minireview summarises recent developments in the biosynthesis of diterpenes by diterpene synthases in bacteria. It is structured by the class of enzyme involved in the first committed step towards diterpenes,starting with type Id iterpene synthases,f ollowed by type II enzymes and the more recently discovered UbiA-related diterpene synthases.Aspecial emphasis lies on the reaction mechanisms of diterpene synthases that convert simple linear precursors through cationic cascades into structurally complex, usually polycyclic carbon skeletons with multiple stereogenic centres.Afurther main focus of this Minireview is adiscussion of howt hese mechanisms can be unravelled.…”

Enzymatic Synthesis of Methylated Terpene Analogues Using the Plasticity of Bacterial Terpene Synthases

“…During the past decade the genomesequences of many bacteria and fungi becamea vailable, which allowed for the discovery and characterisation of various terpene synthases (TSs). [1][2][3][4][5][6][7] Canonical TSs catalyse the conversion of isoprenoid diphosphates with the general formula (C 5n H 8n+ +1 )OPP including dimethylallyl( DMAPP, n = 1), geranyl (GPP, n = 2), farnesyl (FPP, n = 3), geranylgeranyl (GGPP, n = 4) and geranylfarnesyl diphosphate (GFPP, n = 5) into terpenes. For the larger precursors (n > 1) the products are usually (poly)cyclic and contain multiple stereogenic centres.T he TS-catalysed transformations proceed through substratei onisation by abstraction of diphosphate or by protonation, followed by ac ationic cascade including cyclisation reactions, hydride or proton migrations and skeletal rearrangements.…”