Structural Basis and Enzymatic Mechanism of the Biosynthesis of C_9-from C_(10)-Monoterpenoid Indole Alkaloids

摘要

Plants are an extremely important source of alkaloids, of which over 20000 have been identified to date and classified into a number of distinct families. Thanks to their established therapeutic importance, structural diversity and complex biosynthesis, the monoterpenoid indole alkaloid family has attracted significant interest. Many alkaloids of the ajmalan and sarpagan subfamilies exhibit a C_9- instead of a C_(10)-monoterpenoid unit. Ajmalan-type alkaloids, such as ajmaline, are important therapeutics for the treatment of antiarrhythmic heart disorders. Since, like all monoterpenoid indole alkaloids, the members of these subfamilies are derived from the 3α(S)-glucoalkaloid strictosidine (1), which displays the C_(10) secologanin skeleton, loss of a C1 unit during their biosynthesis must take place somewhere downstream of 1. We report herein the determination of the X-ray crystal structure of polyneuridine aldehyde esterase (PNAE), which gives important insight into the biosynthesis of both subfamilies.