Biosynthesis of Podophyllotoxin

The biosynthetic pathway of podophyllotoxin has not been fully eluded for many years; However, in September 2015, the identity of the six missing enzymes in the biosynthesis of podophyllotoxin was reported for the first time. Several previous studies have suggested a common pathway from conversion of coniferyl alcohol to (+) - pinoresinol in the presence of an electron oxidant by dimerization of the stereospecific free radical intermediate. Pinoresinol is then reduced in the presence of the NADPH co-factor to the first laricerosinol, and finally to the secoisolariciresinol. Lactonization on secoisolariciresinol gives rise to mataisinol. Secoisolariciresinol is believed to be converted to yatein by appropriate quinomethane intermediates, leading to podophyllotoxin.

A sequence of enzymes involved has been reported as a directing protein (DIR), to convert coniferyl alcohol to (+) - pinocresol, which is converted by pinocresol-lariciresinol reductase (PLR) to secoisolariciresinol (-), which is converted by sericoisolariciresinol dehydrogenase (SDH) in (-) - mataisinol, which is converted by CYP719A23 to (-) - pluviatolide, which is probably converted by Phex13114 (OMT1) to (-) - yatein, which is converted by Phex30848 (2-ODD) in (-) - deoxypodophyllotoxin. Although not passing through the last stage of production of podophyllotoxin itself, a combination of six genes from the process has enabled the production of etoposide aglycone in tobacco plants.

 

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