Umbelliferone biosynthesis

Others have also raised the question whether an oxidative cyclisa-tion may not also operate in higher plants. Scott and his collaborators on the basis of model reactions thus postulated the involvement of an intermediate spirolactone (69) in umbelliferone biosynthesis but subsequent tracer studies did not support this theory. 

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... 

Coumarins and isocoumarins appear to be of varied origins. Simple coumarins, such as umbelliferone, are formed by the shikimic acid pathway in which hydroxylation of p-hydroxycinnamic acid occurs. Other coumarins, for example alternariol (690), are derived from a polyketide unit, as are a number of chromanones, chromones, pyranones and isocoumarins (B-78MI22400). The biosynthesis of 5-hydroxy-2-methylchromone has been shown to involve the chromanone (60JCS654). However, isocoumarins are also derived from the mixed acetate-shikimate route, through initial cyclization of the polyketide and subsequent lactonization. 

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. 

Biosynthesis of Phenylpropanoids and Related Compounds 203 4.3.1.2 Alkylated umbelliferone... 

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. 

Biosynthesis See umbelliferone the furan ring originates from activated isoprene (dimethylallyl pyrophosphate). Key step in psoralene biosynthesis is the oxidative dealkylation of (+)marmesine, which in one step is converted to psoralene and acetone by a cytochrome P450 enzyme. 

Biosynthesis 7-Hydroxycoumarin ( umbelliferone) is formed on the shikimic acid pathway and geraniol is the precursor of the side chain. 

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). 

Direct evidence for the formation of coumarin from shikimate came from the radiotracer experiments of Kosuge and Conn in 1959, and they and others have also demonstrated cinnamic acid and a number of its ring-oxygenated derivatives, well known to originate from shikimate, to be precursors of various coumarins. The committed step in the biosynthesis of coumarins is hydroxylation of the benzene ring ortho to the side-chain of a cinnamic acid. In a few species the substrate is cinnamic acid itself, leading to the formation of coumarin, but for most coumarins, which bear 7-oxygenation, it is known or assumed that p-coumaric (4 -hydroxycinnamic) acid is the substrate, with discrete enzymes involved in the two cases. The product in the latter instance is 7-hydroxycoumarin (umbelliferone) ( 2, Fig. 1), and thus it is this compound rather than coumarin which, from the biosynthetic standpoint, is the parent compound of the vast majority of coumarins. 

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,... 

All findings up to now indicate that all other coumarins are formed in the same way from the corresponding substituted cinnamic acid, p-Coumaric acid furnishes umbelliferone, caffeic acid aesculetin and ferulic acid scopoletin (Fig. 99). Thus, our reaction scheme (Fig. 98) is generally valid, the appropriate ring substituents have simply to be inserted. The mode of biosynthesis provides us with an explanation of the fact that the most important cinnamic acids and coumarins exhibit the same pattern of substitution. 

Consequences for the so-called segregation model ofisoprenoid biosynthesis The presence of such alternative pathways as outlined above could provide a further explanation for the observations obtained with the HMGR inhibitor mevinolin, viz. its great efficiency in blocking cytoplasmic sterol biosynthesis, but its low efficiency to affect ubiquinone biosynthesis, and its practically complete inefficiency to block the accumulation of isoprenoids and prenyl lipids of the chloroplast (summarized and discussed earlier 14, 17]. It could also explain the puzzling observation that, in contrast to phytosterols, prenyl-subsituted coumarins were not labeled from [2- ]acetate or [2- C]MVA in elicitor-treated cultures oiAmnd majus, suggesting that the DMAPP needed for the (plastid ) umbelliferone dimethylallyl transferases (EC 2.5.1.3) is formed from IPP synthesized de novo within the plastid, rather than from IPP imported into the plastid from the cytosol [86]. Elicitor-induced inhibition of phytosterol biosynthesis should occur by specific inhibition of one of the enz)ones on the c) osolic pathway from MVA to DMAPP. 

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