Furanocoumarins, biosynthesis

Stanjek V, Piel J, Boland W (1999) Biosynthesis of furanocoumarins melvalonate-independent prenylation of umbelliferone in Apium graveolens (Apiaceae). Phytochemistry 50 1141-1146 Steinberg PD (1992) Geographical variation in the interaction between marine herbivores and brown algal secondary metabolites. In Paul V (ed) Ecological roles of marine natural products. Comstock, Ithaca, pp 51-92... 

Larbat R, Kellner S, Specker S, Hehn A, Gontier E, Hans J, Bourgaud F, Matern U (2007) Molecular cloning and functional characterization of psoralen synthase, the first committed monooxygenase of furanocoumarin biosynthesis. J Biol Chem 282 542-554... 

The enzyme that catalyses the conversion of DMAPP and umbelliferone into 6-dimethylallylumbelliferone, the first reaction specifically directed to the biosynthesis of linear furanocoumarins, has been isolated394 from suspension cultures and young leaves of Ruta graveolens. The particulate enzyme could utilize neither herniarin as a substitute for umbelliferone nor GPP in place of DMAPP. 8-Dimethylallylumbelliferone, which is an intermediate in the formation of the angular furanocoumarins, was not formed by these preparations. 

Sites of biosynthesis are compartmentalized in the plant cell. While most biosynthetic pathways proceed (as least partially) in the cytoplasm, there is evidence that some alkaloids (such as coniine, quinolizidines and caffeine), furanocoumarins and some terpenes (such as monoterpenes, diterpenes. 

Haulfe, K.D., Hahlbrock, K. and Scheel, D. (1986) Elicitor-stimulated furanocoumarin biosynthesis in cultured parsley cells S-adenosyl-L-methionine bergaptol and S-adenosyl-L-methionine xanthotoxol O-methyltransferases. Z. Naturforsch., 41c, 228-39. 

Hehmann, M., Lukacin, R., Ekiert, H. and Matem, U. (2004) Furanocoumarin biosynthesis in Ammi majus L. Cloning of bergaptol O-methyltransferase. Eur.. Biochem., 271, 932 0. 

Stanjek, V. and Boland, W. (1998) Biosynthesis of angular furanocoumarins mechanism and stereochemistry of the oxidative dealkylation of columbianetin to an-gelicin in Heracleum mantegazzianum (Apiaceae). Helv. Chim. Acta, 81,1596-607. 

Furanocoumarins are present in Ficus carica, Apium graveolens, Ruta graveolens and Angelica gluca. Marmelosin present in Aegle marmelos is the precursor compound for psoralen biosynthesis. Marmesin, another furanocoumarin, has been reported to be significant source of psoralen. 

Furanocoumarins are extremely toxic. They are known to cause photo-toxicity if not used under medical supervision. Furanocoumarins bind to DNA of the cell and interacts with fats and proteins. Phenylalanine, Umbelliferon, a hydroxycoumarin and isoprene, are precursor compounds for furanocoumarin biosynthesis. The furanocoumarins have shown antibacterial activity against Escherichia coli and Micrococcus luteus. They are hepatotoxic also. 

Volker, S., P. Joem, and W. Boland (1999). Biosynthesis of furanocoumarins Mevalonate independent prenylation of umbelliferone in Apiunt graveolens (Apiaceae) Phytochemistry SO, 1141-1145. 

C,2,3- H2]Dictamnine [as (145)] was efficiently incorporated into skim-mianine (146) without change in isotope ratio. This corroborates the conclusion that dictamnine is an intermediate in skimmianine biosynthesis and that, as in the formation of the furanocoumarins, ° aromatic hydroxylation occurs after formation of the furan ring. 

Interest in enzyme stereospecificity and the stereochemistry of prochiral centres, such as the methylene groups of mevalonic acid, has necessitated more precise definitions of the stereochemistry of the various molecules involved and of the enzymological consequences. The use of multiply labelled mevalonic acid in terpenoid and steroid biosynthesis has been reviewed by Hanson. The Proceedings of the 1970 Phytochemical Society symposium have been published. They include a general discussion of terpenoid pathways of biosynthesis by Clayton and specific chapters on monoterpenoids, diterpenoids, eedysones, carotenoids, isoprenoid quinones, and chromanols. Other reviews concerning biosynthesis have appeared on furanocoumarins, indole alkaloids, monoterpenoids, and diterpenoids. ... 

The formation of benzofuranoid and analogous ring systems seems to follow a common pathway. In the rotenoid amorphigenin (25) the sequence is shown in Scheme 3. Here all five carbon atoms are retained. With the furanocoumarins there is a loss of three carbon atoms but the initial stages are probably analogous. Several studies on these sequences are summarized in Scheme 4. A similar process occurs in the biosynthesis of furanoquinoline alkaloids (see Scheme 5). 

Biological Activity Furanocoumarins Biosynthesis of Furanocoumarins Systematic and Phylogenetic Importance of Furanocoumarins... 

Coumarin biosynthesis involves formation of PAL and 4-coumarate CoA ligase which is light and elicitor inducible. Cells of P. crispum respond by producing the linear furanocoumarins psoralen (17), bergapten (18), and xanthotoxin (19) (Fig. 9.6), as well as other furanocoumarins (Ellis, 1988). The relative amounts of furanocoumarins in the mixture was changed by use of different fungal elicitor sources. 

Angular furanocoumarins are derived by prenylation at the 8-position of umbelliferone followed by cyclization via similar intermediates, although experimental evidence is not as good as for linear furanocoumarin biosynthesis. Columbi-anetin (28) (derived by 8-prenylation) is involved in the biosynthesis of angelicin and derived angular furanocoumarins (Fig. 9.3). 

Brown, S. A. and W. Steck, 7-Demethylsuberosin and osthenol as intermediates in furanocoumarin biosynthesis. Phytochemistry, 12, 1315-1324 (1973)... 

In more recent studies this Italian group has examined further certain aspects of linear furanocoumarin biosynthesis. The isomer of rutaretin, 5-hydroxymarmesin (19), was shown by the use of a tritiated substrate to serve as a precursor of bergapten (20) in R. graveolens, and also in Ficus carica. 5-Hydroxymarmesin, although a recognized natural product, has apparently not been reported from these two species, and for this reason its status as a natural intermediate, in contrast to rutaretin, remains uncertain. 

Methyltransferases of furanocoumarin biosynthesis. Arch. Biochem. Biophys. 188 272-281. 

Hydroxyisopropyl dihydrofuranocoumarins (26, R=H) are well established as intermediates in the biosynthesis of both angular and linear furanocoumarins. This intermediate requires the removal of the terminal three carbons of the isopentenyl group (Fig. 5) to give the furanocoumarins, or 2. Current views on the method for removal of the hydroxyisopropyl group involves a role for a 3 -hydroxy derivative (29). Indirect evidence supporting this view comes from work on the parallel biosynthesis of furanoqui-noline alkaloids. Only one label is lost when 3 ,3 -doubly labeled analogue of 2 is fed to the plant.This result precludes an intermediary role for a 3 -keto marmesin. 

There has been much interest in the biosynthesis of coumarins bearing isoprenoid-related substituents these are now considered to be mevalonate derived 338, 340, 341). In part this has stemmed from the important skin-sensitizing activity of some furanocoumarins which has been correlated with their photoreactivity towards pyrimidine bases of DNA 409). The proposal by Birch (72) that the two extra carbon atoms of the furan ring are derived by loss of three carbon atoms from an intermediate hydroxyisopropyldihydrofuranocoumarin has received considerable experimental support in recent years 152, 198, 199). Indeed, it has now been established that ( + )-marmesin (103), formed from umbelliferone (2) via 7-demethylsuberosin (86) is a key intermediate in the biosynthesis of linear furanocoumarins 105, 107,... 

V. Stanjek, M. Miksch, W. Boland, Stereoselective synthesis of deuterium labelled marmesins valuable metabolic probes for mechanistic studies in furanocoumarin biosynthesis. Tetrahedron 53 (1997) 17699-17710. 

Stanjek, V., Piel, J. and Boland, W. (1999b) Biosynthesis of furanocoumarins mevalonate-independent prenylation of umbeUiferone in Apium graveolens (Apiaceae). Phytochemistry, 50, 1141-1145. 

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