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Phytochemicals of the Month
Special expanded
section on Phytoestrogens and
Human Health
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Why are isoflavones estrogenic?
Isoflavones in plants are made via
different biosynthetic pathways than those which make estrogens in the human
body; the two are not closely related chemically. However, both types of
molecules have certain structural similarities that enable them to bind with
mammalian estrogen receptors. These similarities include:
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The A and C rings of the isoflavones are similar to the
A and B rings of estradiol (pink).
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The actual distance between the two
hydroxyl groups (blue) on both molecules is nearly identical; these hydroxyl
groups are critically located to enable binding to the estrogen receptor
protein.
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Both molecules have similar polarities
and molecular weights.
The structures below represent
formononetin and biochanin A, the isoflavones from red clover. They are
quite similar to daidzein and genistein, with the same fused 6-member A and
C rings and the same pattern of hydroxyl groups on the A rings:
Both of these molecules, however, are considerably less likely to bind to
estrogen receptors than are daidzein or genistein. This is attributed to the
hindering presence of the methoxy groups (instead of hydroxyl groups) on the
B rings of the molecules (blue). In vivo, formononetin is converted into
daidzein and biochanin A into genistein by colon bacteria. |
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Biosynthetic derivation of the isoflavones
Like all flavonoids, isoflavones are
constructed via two different biosynthetic pathways: the A ring is formed from three acetate units
(via the malonic acid pathway) and the B ring with
the 3-carbon bridge is made from a phenylpropane unit via the shikimic acid
pathway. The enzyme chalcone synthase condenses these units, forming a
chalcone which is the precursor of all the other types of flavonoids.
Chalcone isomerase then acts upon the chalcone to turn it into a flavanone
(skeleton below on left), which is the immediate precursor to the
isoflavones.
The flavanone (specifically,
liquiritigenin --> daidzein and naringenin -->genistein) is subsequently
oxidized by the cytochrome P450-dependent enzyme, 2-hydroxyisoflavanone synthase
(cofactors: NADPH, O2). During this transformation the
aryl ring migrates from position 2 to position 3. Coumestrol (a coumestan)
is derived from the basic isoflavone skeleton.
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Glucose conjugates of isoflavones in plants
Most isoflavones naturally occur as various glucosides,
acetylglucosides, or malonylglucosides. Free aglycones are present, but in
small quantity.
These examples show the various forms of daidzein (7,4'-Dihydroxyisoflavone);
the other major glucose conjugates are:
| Aglycone |
Glucoside |
Acetylglucoside |
Malonylglucoside |
genistein
(5,7,4'-Trihydroxyisoflavone) |
genistin
(genistein-7-O-beta-D-glucoside) |
6"-acetylgenistin
(genistein-7-O-beta-D-glucoside-
6"-O-acetate) |
6"-malonylgenistin
(genistein-7-O-beta-D-glucoside-
6"-O-malonate) |
glycitein
(7,4'-Dihydroxy-6-methoxyisoflavone) |
glycitin
(glycitein-7-O-beta-D-glucoside) |
6"-acetylglycitin
(glycitein-7-O-beta-D-glucoside-
6"-O-acetate) |
6"-malonylglycitin
(glycitein-7-O-beta-D-glucoside-
6"-O-malonate) |
biochanin A
(5,7-Dihydroxy-4'-methoxyisoflavone) |
sissotrin
(biochanin A-7-O-beta-D-glucoside) |
6"-acetylsissotrin
(biochanin A-7-O-beta-D-glucoside-
6"-O-acetate) |
6"-malonylsissotrin
(biochanin A-7-O-beta-D-glucoside-
6"-O-malonate) |
formononetin
(7-Hydroxy-4'-methoxyisoflavone) |
ononin
(formononetin-7-O-beta-D-glucoside) |
6"-acetylononin
(formononetin-7-O-beta-D-glucoside- 6"-O-acetate) |
6"-malonylononin
(formononetin-7-O-beta-D-
glucoside-6"-O-malonate) |
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Biosynthetic derivation of the lignans
The precursors of the lignans are polyphenolic molecules
known as hydroxycinnamyl alcohol monomers. In the formation of the dietary
lignans secoisolariciresinol and matairesinol, the specific monomer is
coniferyl alcohol, two molecules of which are transformed into pinoresinol
by phenolic oxidative coupling. The dimeric pinoresinol then undergoes ring
opening and reduction to become secoisolariciresinol. Matairesinol is made
from secoisolariciresinol by oxidation and lactone ring formation:
Secoisolariciresinol generally occurs in
plants as the diglucoside ('SDG'). |
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General references
Bruneton, Jean.
Pharmacognosy Phytochemistry Medicinal Plants. 2nd ed. Lavoisier
Publishing: New York, 1999.
Dewick, Paul. Medicinal Natural Products: A Biosynthetic Approach.
2nd ed. John
Wiley & Sons, Ltd: Chichester, UK., 2002.
Harborne, Jeffrey B.,
Herbert Baxter, and Gerard P. Moss. Phytochemical Dictionary: A
Handbook of Bioactive Compounds from Plants. 2nd ed. Taylor & Francis:
London, UK. 1999.
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