Sesquiterpene synthases: Passive catalysts or active players?

Abstract

Sesquiterpene synthases catalyse the metal dependent turnover of farnesyl diphosphate to generate a class of natural products characterised by an enormous diversity in structure, stereochemistry, biological function and application. It has been proposed that these enzymes take a passive role in the reactions they catalyse and that they serve mostly as stereochemical templates, within which the reactions take place. Here, recent research into the structure and function of sesquiterpene synthases and the mechanisms of the reactions that they catalyse will be reviewed to suggest that these fascinating enzymes play multifaceted active roles in what are arguably the most complex biosynthetic reactions.

Unique Biosynthesis of Sesquarterpenes (C35Terpenes)

“…34) These results suggest not only that two distinct pathways (Fig. 4, pathways A and B), which use E,E-FPP and E,E,E-GGPP respectively as substrates of Mvan 3822, are utilized to biosynthesize sesquarterpenes (13)(14)(15)(16)(17)(18) in the cells, and also that polyprenyl reductase (PR) can reduce both the Z and the E double bonds at C-14 of compounds 20 and 21. 34) In 2012, a new sesquarterpene, 18, was isolated from M. chlorophenolicum cells grown to stationary phase.…”

“…34) In 2012, a new sesquarterpene, 18, was isolated from M. chlorophenolicum cells grown to stationary phase. 35) The absence of compound 22 suggests that the main sesquarterpenes (13)(14)(15) are biosynthesized only via pathway B in the stationary phase, in contrast to the logarithmic growth phase, in which both pathway A and pathway B are involved. 35) In addition, our findings suggest that stepwise reduction of the polyprenyl group in sesquarterpene biosynthesis might proceed in a different order from that in chlorophyll biosynthesis.…”

“…31) It has been reported that many terpene cyclases have broad substrate specificities, and that other classes of terpenes have been created in vitro. [2][3][4][5][6][7][8][9][10][11][12][13][14][15] A combination of studies identifying enzymatic products biosynthesized from unusual substrates and the analysis of genome sequences should lead not only to the discovery of additional functions of these enzymes in the organism, but also to the identification of novel natural terpenoids that have functions in their producers.…”

“…[1][2][3][4][5][6][7][8][9][10][11][12][13][14][15] These compounds including hormones, vitamins, drugs, flavorings, and pigments, are categorized by number of C 5 isoprene units, as follows: hemi-(C 5 ), 1 unit; mono-(C 10 ), 2 units; sesqui-(C 15 ), 3 units; di-(C 20 ), 4 units; sester-(C 25 ), 5 units; tri-(C 30 ), 6 units; and tetraterpenes (C 40 ), 8 units. [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15] In contrast, little is known about C 35 terpenes. To the best of my knowledge, only 19 cyclic and eight linear C 35 terpenes have been identified to date, [16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33]…”

Optimising Terpene Synthesis with Flow Biocatalysis

“…Despite their structural diversity, all sesquiterpenes are synthesised in nature from the common linear precursor farnesyldiphosphate (FDP) ( 1 ) by sesquiterpene synthases (Scheme 1). 3 Sesquiterpene synthases generate the polycyclic core structures of sesquiterpenes, often with several stereogenic centres, in one step through a series of highly sophisticated and elegant reaction cascades that involve cyclisations, additions and rearrangements. The exquisite regio‐ and stereocontrol of sesquiterpene synthases make these enzymes attractive catalysts for the synthesis of this class of natural products.…”