Prediction of the reaction mechanisms of sesquiterpene coumarin synthases supports a direct evolutionary link with triterpene biosynthesis.
Sesquiterpene coumarins are primarily produced by plants of the Apiaceae and Asteraceae families. Farnesylation of 7-hydroxycoumarins such as umbelliferone, scopoletin or isofraxidin yield linear 7-farnesyloxycoumarins that are converted to various cyclic sesquiterpene coumarins by sesquiterpene coumarin synthases (cyclases). The terminal double bond of the linear 7-farnesyloxycoumarins is epoxidized by a sesquiterpene coumarin epoxidase. The diverse 7-(10',11'-oxidofarnesyloxy)-coumarins produced are protonated by various sesquiterpene coumarin synthases to generate a carbocation that initiates cyclization of the farnesyl moiety (A process analogous to the carbocation cascades observed with sesquiterpene synthases and other cyclases involved in the biosynthesis of additional terpene classes, such as the triterpenes). These reaction mechanisms typically include Wagner-Meerwein rearrangements, such as hydride, methyl, and other alkyl shifts, but can also involve more complex processes including Grob fragmentations. Around 260 sesquiterpene coumarins based on 7-farnesyloxycoumarins have been described, but essentially nothing is known about the biosynthetic enzymes involved, i.e., farnesyltransferase, sesquiterpene coumarin epoxidase and synthase. In this review, putative reaction pathways for formation of the carbon skeletons of all known 7-farnesyloxycoumarins-derived sesquiterpene coumarins are presented.