Isoflavones biosynthesis

Diets rich in millet have been associated with endemic goiter in parts of West Africa where millet is a staple. The damage has been attributed to vitexin, a C-glycosyl flavone, that in rats has antithyroid activity and that in vitro inhibits thyroid peroxidase and the free radical iodination step in thyroid hormone biosynthesis. Isoflavones have produced similar antithyroid effects in rats, but clinical studies in adults have not. " However, this remains a possible concern in infants fed soya-based milk-replacers, especially if iodine supply is compromised. 

Figure 5.4. Abbreviated scheme for biosynthesis of major flavonoid subclasses, showing the primary enzymes and substrates leading to different subclasses. Bold-faced, uppercase abbreviations refer to enzyme names, whereas substrate names are presented in lowercase letters. PAL, phenylalanine ammonia lyase C4H, cinnamate 4-hydroxylase 4CL, 4-coumarate CoA ligase CHS, chalcone synthase CHI, chalcone isomerase CHR, chalcone reductase IPS, isoflavone synthase F3H, flavonone 3-hydroxylase F3 H, flavonoid 3 -hydroxylase F3 5 H, flavonoid 3 5 -hydroxylase FNSI/II, flavone synthase DFR, dihydroflavonol 4-reductase FLS, flavonol synthase ANS, anthocyanidin synthase LAR, leucoanthocyanidin reductase ANR, anthocyanidin reductase UFGT, UDP-glucose flavonoid 3-O-glucosyltransferase. R3 = H or OH. R5 = H or OH. Glc = glucose. Please refer to text for more information.

The 2 -hydroxyisoflavones are reduced to the corresponding isoflavanones by a NADPH-dependent isoflavone reductase (IFR). The isoflavanones are the final isoflavonoid intermediates of pterocarpan biosynthesis. Variant IFR activities between species are thought to contribute to the stereochemistry of the pterocarpans produced, in particular, (-l-)-maackiain in P. sativum, (—)-maackiain in C. arietinum, (—)-3,9-dihydroxypterocarpan in G. max, and (—)-medicarpin in M. sativa. The (—) indicates 6aRllai stereochemistry. 

Paiva, N.L. et al., Molecular cloning of isoflavone reductase from pea (Pisum sativum L.) evidence for a 3R-isoflavanone intermediate in (+)-pisatin biosynthesis. Arch. Biochem. Biophys., 312, 501, 1994. 

Yu, O. et al., Metabolic engineering to increase isoflavone biosynthesis in soybean seed. Phytochemistry, 63, 753, 2003. 

Noreen, Y., Two new isoflavones from Ceiba pentandra and their effect on cyclooxygenase-catalyzed prostaglandin biosynthesis, Journal of Natural Products, 61, 8, 1998. 

Flavonoids can be classified according to their biosynthetic origins. Some flavonoids are both intermediates in biosynthesis and end-products, e.g. chalcones, flavanones, flavanon-3-ols and flavan-3,4-diols. Other classes are only known as the end-products of biosynthesis, e.g. anthocyanins, flavones and flavonols. Two further classes of flavonoids are those in which the 2-phenyl side-chain of flavonoid isomerizes to the 3-position (giving rise to isoflavones and related isoflavonoids) and then to the 4-position (giving rise to the neoflavonoids). The major classes of flavonoids, with specific examples, are summarized helow. 

Akashi T, Aoki T, Ayabe S. 2005. Molecular and biochemical characterization of 2-hydroxyisoflavanone dehydratase. Involvement of carboxylesterase-like proteins in leguminous isoflavone biosynthesis. Plant Physiol 137 882-891. 

He X-Z, Dixon RA. 2000. Genetic manipulation of isoflavone 7-O-methyltransferase enhances biosynthesis of 4 -0-methylated isoflavonoid phytoalexins and disease resistance in alfalfa. Plant Cell 12 1689-1702. 

Jung W, Yu O, Lau S-M C, O Keefe DP, Odell J, Fader G, McGonigle B. 2000. Identification and expression of Isoflavone synthase, the key enzyme for biosynthesis of isoflavones in legumes. Nature 18 208-212. 

Liu C-J, Dixon RA. 2001. Elicitor-induced association of isoflavone O-methyltransfer-ase with endomembranes prevents the formation and 7-O-methylation of daidzein during isoflavonoid phytoalexin biosynthesis. Plant Cell 13 2643-2658. 

Lopez-Meyer M, Paiva NL. 2002. Immunolocalization of vestitone reductase and isoflavone reductase, two enzymes involved in the biosynthesis of the phytoalexin medicarpin. Physiol Molec Plant Pathol 61 15-30. 

Scheme 1.1 Pathway for the biosynthesis of the major classes of flavonoids. 1, Chalcone synthase 2, chalcone isomerase 3, flavone synthase 4, flavanone 3-hydroxylase 5, flavonol synthase 6, dihydroflavonol reductase 7, anthocyanidin synthase 8, anthocyanidin glucosyltransferase 9, chalcone-ketide reductase 10, chalcone isomerase 11, isoflavone synthase 12, isoflavone 2 -hydroxylase 13, isoflavone reductase 14, pterocarpan synthase 15, pterocarpan 6a-hydroxylase 16, prenyltransferase 17, prenylcyclase.

HASMM, M.F., HATKAMATSUKA, T EBEUKA, Y SANKAWA, U Reaction mechanism of oxidative rearrangement of flavanone in isoflavone biosynthesis. FEBS Lett., 1990,271,219-222. 

Hakamatsuka, T., Hashim, M.E., Ebizuka, Y. and Sankawa, U. (1991) P450-dependent oxidative rearrangement in isoflavone biosynthesis reconstitution of P450 and NADPH P450 reductase. Tetrahedron, 47, 5969-78. 

Certain phytoestrogens have also been suggested to inhibit enzymes involved in estrogen biosynthesis and metabolism, as well as thyroid biosynthesis. Preliminary studies suggest they inhibit protein kinases and topoisomerases, as well as influence the cell cycle and subsequent proliferation, differentiation and apoptotic pathways. Interest in phytoestrogens, such as isoflavones, has increased since they are reported to exhibit some nonhormonal effects, such as antioxidation. 

Fig. 4 Biosynthesis of isoflavonoids (pterocarpans) via isoflavones from phenylpropanoid pathway...

---