Podophyllotoxins biosynthesis

Xia Z-Q, Costa MA, Proctor J et al (2000) Dirigent-mediated podophyllotoxin biosynthesis in Liman jlavum and Podophyllum peltatum. Phytochemistry 55 537-549... 

Figure 4 Redox reactions in biosynthetic pathways. A one-electron oxidation of two coniferyi aicohoi monomers is the initiating step in podophyllotoxin biosynthesis, and a simiiar one-eiectron oxidation piays a key role in the biosynthesis of the aikaioid morphine. Redox reactions are also used to crosslink nascent scaffoids, as shown for vancomycin, or to add oxygen-based functionality to reduced scaffoids, as shown for taxoi.

Very recently Dewick has begun a thorough investigation of podophyllotoxin biosynthesis in Podophyllum hexandrum. Cinnamic and ferulic acids are each incorporated equally into both halves of the molecule, the carbon of the 0-methyl group of ferulic acid being retained by both ring A and ring C (Scheme 4). ... 

Costa, M.A. et al. (2013) Next generation sequencing in predicting gene function in podophyllotoxin biosynthesis. J. Biol Chem., 288, 466-479. 

Lignans represent an extremely diverse group of compounds. This is the result of both structural diversity and stereo-selective biosynthesis. One particular plant species generally makes only one enantiomer of a particular compound. The other enantiomer may be synthesized by a different species. As a consequence, it is virtually impossible to summarize the biosynthesis of lignans in general. Instead, the focus here will be on the biosynthesis of the lignan podophyllotoxin in a number of different plant species, as an illustration of the different biosynthetic routes that can be used to synthesize the same compound. 

In addition to podophyllotoxin itself, closely related compounds, such as 5-methoxypodophyllotoxin (3.89), can be used as a precursor for anti-cancer drugs. Linum species (flax, linseed) can produce podophyllotoxin or substituted podophyllotoxins in tissue culture with yields of up to 0.35% of dry weight. The biosynthesis of 5-methoxypodophyllotoxin in Linum flavum was investigated by Xia et al. (2000), whereas Seidel et al. (2002) investigated podophyllotoxin (3.86) production in cell cultures of Linum album. 

Synthesis of podophyllotoxin (3.86) in cell culture of Linum album results in yields comparable to those of the most efficient tissue cultures of Podophyllum hexandrum. In order to further improve L. album cultures, Seidel et al. (2002) investigated the biosynthesis of podophyllotoxin (3.86). They fed a number of labeled compounds that to L. album cell cultures to identify which of these compounds could be used as precursors to podophyllotoxin. They determined that the substitution pattern on the benzene ring is critical. The substitution has to be either 3-methoxy, 4-hydroxy, as in ferulic acid (3.33), or, alternatively, 3,4-methylenedioxycinnamic acid (3.90) can serve as precursor. The precursor of podophyllotoxin in L. album appears to be deoxypodophyllotoxin (3.83), based on the higher level of isotope incorporation in the latter compound. This means that 7-hydroxymatairesinol, the precursors of 5-methoxypodophyllotoxin in L. flavum (Xia et al., 2000), is not a precursor of podophyllotoxin in L. album. 

Figure 4.11 Proposed biosynthetic steps involved in the biosynthesis of podophyllotoxin(-glucoside) and 6-methoxypodophyllotoxin(-glucoside). Steps catalyzed by yet unidentified enzymes are shown with dashed arrows. Enzymes involved are as follows (1) deoxypodophyllotoxin 7-hydroxylase, (2) deoxypodophyllotoxin...

Seidel V, et al. Biosynthesis of podophyllotoxin in Linum album cell cultures. Planta 2002 215 1031-1039. 

Little is known about the tissue and subcellular compartmentation of lignan biosynthesis in Podophyllum. In vitro cultured cells of P. emodi are capable of synthesizing podophyllotoxin from coniferyl alcohol, implying... 

Jackson D E, Dewick P M 1984 Biosynthesis of Podophyllum lignans. I. Cinnamic acid precursors of podophyllotoxin in Podophyllum hexandrum. Phytochemistry 23 1029-1035... 

Podophyllum peltatumJLinum flavum by Lewis and coworkers [13a] using radiolabeled substrates, whereas (-)-matairesinol (45) that serves as a biosynthetic precursor for (-)-podophyllotoxin (39) had been also determined earlier by Dewick and coworkers [13b]. These late-stage transformations include modifications of two aryl rings and subsequent Friedel-Crafts alkylation of the resultant yatein (46) just like that described from 36 to 37 (Scheme 10.5). Finally, the regio- and stereoselective hydroxylation of (-)-deoxypodophyllotoxin (47) completes the biosynthesis of (-)-podophyllotoxin (39). 

---