BIOSINTESIS

FLAVONOID

OCCURRENCE

flavonoids are widely distributed in the flora

they can be found in petals, crops, seeds, leaves, stems,

roots and barks

it is the reddish braunish - yellowish colour of

heartwood

flavonoids of ferns are C-methyl derivatives

glycoflavonoids can be isolated from see-weeds

inferior plants and mushrooms have them only very

rarely

microorganisms and algae species do not synthetize

STRUCTURE OF FLAVONOIDS
Polyphenols, namely favonoids are low molecular weight substances
The skeleton can be represented as the C6 - C3 - C6 system
Three main groups can be distinguished on the places of phenyl ring.

The chemical structure of

flavonoids are based on a
C15
skeleton
with
a
chromane ring bearing a
second aromatic ring B in
position 2, 3 or 4.

The oxidation state of propane chain means the difference.

Oxidation degree rises from 0 to 6. (Tetrahedron, 8, 336, 1960.)

SYNTHESIS OF FLAVONOIDS

Flavonoids are synthesized by the phenylpropanoid metabolic pathway in which the

amino acid phenylalanine is used to produce 4-coumarate-CoA.
This can be combined with malonyl-CoA to yield the true backbone of flavonoids, a
group of compounds called chalcones, which contain two phenyl rings.
Conjugate ring-closure of chalcones results in the familiar form of flavonoids, the
three-ringed structure of a flavone.

The metabolic pathway continues through a series of enzymatic modifications to

yield flavanones dihydroflavonols anthocyanins.
Along this pathway, many products can be formed, including the flavonols, flavan3-ols, proanthocyanidins (tannins) and a host of other various polyphenolics.

ENZIMATIC CONVERSION OF NARINGENIN

TO APIGENIN

EC 5.5.1.6 chalcone isomerase

EC 1.14.11.22 flavone synthase

ENZIMATIC CONVERSION OF TAXIFOLIN TO QUERCETIN

EC 1.14.11.23 flavonol synthase

ENZYMATIC CONVERSION FROM

DIHYDROKAEMPHEROL TO
LEUCOPELARGONIDIN

EC 1.1.1.219 dihydrokaempferol 4-reductase

SYNTHESIS OF FLAVONOIDS
EC 1.1.1.219 dihydrokaempferol 4-reductase
EC 1.14.11.9 flavanone 3-dioxygenase
EC 1.14.11.22 flavone synthase
EC 1.14.11.23 flavonol synthase
EC 1.14.13.21 flavonoid 3'-monooxygenase
EC 1.14.13.88 flavonoid 3',5'-hydroxylase
EC 1.17.1.3 leucoanthocyanidin reductase
EC 5.5.1.6 chalcone isomerase
http://www.chem.qmul.ac.uk/iubmb/enzyme/reaction/phenol/flavonoid.html

FLAVONOIDS ARE DIVIDED INTO GROUPS

According to the IUPAC nomenclature, they can be classified into:
flavone:

2-phenylchromen-4-one

flavonol:

(3-hydroxyflavone) 3-hydroxy-2-phenylchromen-4-one

flavanone: 2,3-dihydro-2-phenylchromen-4-one
flavanonol: (3-hydroxyflavanone) 3-hydroxy-2,3-dihydro-2-phenylchromen-4-one
isoflavone
anthocyanidin

other flavonoids

proantocianidin
catechin
chalcone
dihydrochalcone
aurone

Both the oxidation state of the heterocyclic ring and the position of ring B are
important in the classification.

ANTHOXANTHINES ARE THE REAL

FLAVONOIDS
Natural derivatives from benzo--pyron stucture are
considered as flavonoids by certain researchers.
These molecules are anthoxantines.
benzo--pyron
chromon

-pyron

SPECIAL FLAVON
DERIVATIVES

cumaroflavones

isocumaroflavon

furanoflavonoids

biflavones

coumestan derivatives

rotenoids

BIOCHEMICAL PATHWAY
OF THE FORMATION OF
ROTENONE

blue: carbons derived from methionine

red: carbons derived from prenyl (isoprenoid).

REASON FOR THEIR VARIETY

OH groups

number and position of

O-methyl, O-alkil, O-glycosyl-groups

variance of glycosyl groups, acylation grade

with or without conjugated double bonds

The most often occuring substituents can bond to C3 -, C5 , C7 -, C3 -, C4 atoms.

Sugars can bond:

through oxygen atom (O-glycosides)

directly to C-atom (C-glycosides)

Antocyanides are always in their glycoside forms in vacuoles (in cell fluids)
catechines and procyanidines can be stored in their aglycone forms
(tannic acid holders, dissolved in essential volatile oils)

THE ROLE OF FLAVONOIDS IN PLANTS

Flavonoids are the secondary metabolites of plants, and they are providing
the colour and flavour materials.

protect against
UV-radiation
fungus- , insect- and snail pests

they are signal for N-bound bacteria

they modify enzyme reactions

75% of Angiospermae contain kaempferol and quercetin and 10% of them
myricetin.

kaempferol

quercetin

myricetin

THE MOST OFTEN OCCURING GLYCOSIDE

rutin

Rutine can be found in 50% of Angiospermae.

Quercetin is the aglycone form of a number of other flavonoid
glycosides, such as rutin and quercitrin, found in citrus fruits,
buckwheat and onions.
Quercetin forms the glycosides quercitrin and rutin together with
rhamnose and rutinose, respectively.

BIOFLAVONOIDS HAVE BIOACTIVITY

flavone, flavonol, flavanone, flavanonol
2-phenyl-benzo--pyron

High concentration of
quercetin in in vitro
isoflavone
causes
3-phenyl-benzo--pyron experiments
DNA mutations in spite
of that epidemiological
studies declare that
this
flavonoid
consuming
prevents
atherosclerosis, infarct
and others [Dunnick
catechin

anthocyanidin

1998, Williams 2004].

Recent in vitro
examinations strenghten the
antiproliferative effects of
prenylated naringenin
(Humulus lupulus L., hops)
on prostate tumour cell line
culture.
(Phytomedicine. 13 (9-10), 732-4.
2006.)

Oxygen of pyrane ring is quaterner.

Oxoniumbases with acids form salines.

20 dkg soylent contains ca. 300

mg izoflavones.

CONDITIONS OF ANTIOXIDANT
PROPERTY

Fenolic antioxidants can function free radical scavengers and

metal chelators.

Flavonoids are highly effective scavengers of all types of oxidizing

radicals.

Rate constant of quercetin with superoxide anion is 0.9x10 5 at pH

7.5. The arised fenoxy radical is a relatively stable molecule.

This molecule limits the metal catalysed degradation of

hydroperoxides.

CHELATING ABILITY OF FLAVONS AND

FLAVANONS

Conditions of chelating property:

3, 4- dihydroxy configuration

carbonyl group at the position 4

free OH-groups at 3- and 5 positions

MESOMER STRUCTURE OF QUERCETIN AROXYL

RADICAL

PHYSIOLOGICAL ACTIVITY OF
FLAVONOIDS
Flavonoids have been referred to as "nature's biological
response modifiers" because of strong experimental
evidence of their inherent ability to modify the body's
reaction

antioxidant and /or scavenger activity

immunomodulating and antiinflammatory effects
anti-asthmatic and anti-allergic effects
anti-viral and anti-bacterial and anti-fungal effects
oestrogen activity (isoflavonoids)
influencing effect on mutagenicity and
carcinogenicity
hepatoprotective effect
effects on circulation, modification of permeability

ADDITIONAL INFO OF
FLAVONOID

SILIBININ INCREASES
SYNTHESIS OF RNA
POLIMERASE
(Flavanolignane)

BANNED!
Catechol-type antioxidant was
used in cases of alcoholic liver
diseases.

CATERGEN

It was also available in Hungary, but became

banned because it caused haemolytic anaemia.
Depending on concentration, catergen inhibits the
activities of Mg++ ATP-ase and Na+K+ ATP-ase.

METABOLISM OF FLAVONOIDS DEPENDS ON SEVERAL

FACTORS
Only 1 % of the original form of flavonoids can get into the
circulation.

stucture, oxidation state

rate of glycosylation /acylation

conjugation property

rate of polymerisation

antioxidant property

rate of absorption

bacterial enzyme activity

effects of their derivatives are often different from natural

molecules
(Hertog 1993, Hollman 1995, Breinholt 1999.)

WHAT HAPPENS WITH FLAVONOIDS IN OUR

SYSTEM?
Flavonoids are extensively metabolised,
metabolites arise on intestinal absorption.

and

their

Flavonoids are also transformed into phenolic acids by the

enzymes of colonised gut microbes.
These phenolic acids are also absorbed and metabolised in
the liver.
Generally, flavonoids may undergo conjugation, oxidation
and P450-related transformation intracellularly.
Glucuronide and sulfate conjugates are formed with the
majority of flavonoids in the small intestine and in the
liver.

BIOTRANSFORMATION OF FLAVONOIDS
IN MICROSOMES

The liver is the main detoxicating tissue, where the elimination of

exogenic toxic agents happen. Mixed functioning oxidases are localised
in the endoplasmic reticulum and they can catalyse a lot of oxidation
reactions. They too have the main role of decompositioning lipid
peroxidation endproducts.

TRANSFORMATION OF LUTEOLIN
BY BACTERIA AND MICROSOME
Flavonoid glycosides can unergo changes because
of the effects of bacterial enzymes colonised in the
bowel in the terminal ileum and colon.

Mixed functioned monooxigenases are able

to modify flavonoids in the liver, bowel,
kidneys and skin.

PLASMA LEVELS OF FLAVONOIDS

(mg/ttg)

(ug/ml)

quercetin

65

<0,1

Gungler (1975)

(+) - catechin

32

0,064

Lee (1995)

3-methoxycatechin

30

11

Hackett (1985)

diosmin

10

0,4

Cova (1992)

rutin

1,4

0,09

Hollman (1997)

REGULATION OF CELL CYCLE DEPENDS ON

REDOX HOMEOSTASIS
Flavonoids can influence the redox homeostasis in several steps:
in PG-biosynthesis
in leukotriene biosynthesis
in NF-B translocation to the
nucleus
in PKC activity and
in PI3-kinase activity in signal
We can simply say that free
radicals in small concentrations
may cause apoptosis, and in large
quantities necrosis.

transduction
in MMP-ase activity in extracellular space in tumour

BIOSYNTHESIS OF PROSTAGLANDINS

Kempferol inhibits
COX2-enzyme

BIOSYNTHESIS OF LEUKOTRIENES

Quercetin inhibits the

activities of
lipoxygenases,
therefore they have
anti-inflammatory
properties.
Prenylated flavonoids
can inhibit the 15lipoxygenase activity.

FLAVONOIDS AND SIGNAL TRANSDUCTION

The polyphenol like compounds inhibit signal transduction pathways, the TNFmediated
activation of NF-B pathway, partly through the inhibition of IB kinase and IL-1
activated NF-B pathway, which is a partly distinct route. NF-B activation by IL-1
requires an IL-1 receptor-associated protein kinase activity [Croson 1995].

LOCATION OF FLAVONOIDS IN THE ACTIVE CENTRE

OF PI3-KINASE

Flavonoids are the potential inhibitors of protein kinases.

Glycosylation of aglicons moderate the inhibitory effect.
Small molecular alterations can strenghten the inhibitory activity and
selectivity.
It is hard to predict between structure and function any better.

FLAVONOIDS IN THE SIGNAL TRANSDUCTION

PROLIFERATION AND SPREDING OF TUMOUR DEPENDS ON

ACTIVITIES OF MATRIX-METALLOPROTEINASES

In the formation of
extracellular the matrix,
collagenes take part in the
delimitation of individual
cell populations.
Zn-containned
matrix
metalloproteinases do the
continous renewal of the
extracellular matrix.
Tissue inhibitors and alpha
2- macroglobuline inhibit
Flavonoids could also induce mechanisms the MMP ases.

that help kill cancer cells and inhibit tumor

invasion.

BONDING OF FLAVONOIDS TO THE

MATRIX METALLOPROTEINASE-9

Flavonoids are potent inhibitors of MMP-ases.

There is small difference concerning the inhibitory effect
in the case of flavonoid aglicons.
Glycosylation increases the inhibitory effect.
The connection between structure and function can be predicted well.

FLAVONOIDS AND SIGNAL

TRANSDUCTION
Flavonoids can modulate
the activity of protein
kinase and lipid kinase
signaling cascades.

NF-B, JNK and p53 signaling proteins

play an important role in apoptotic
death and free radicals and metals are
very important mediators in the
apoptotic process as well.

Direct
and
indirect
inhibitory
actions
of
flavonoids within ERK1/2
and Akt/PKB pathways
could initiate cell death,
whereas inhibitory actions
within JNK pathways are
more
likely
to
be
protective.
[Agullo 1997, Gamet-Payrastre
1999,]

DATA CONCERNING OF FLAVONOIDS

Consuming vegetables and fruits containing one gram of
flavonoid and polyphenol per day is advised.
According to surveys in different countries, people
consume flavonoids in the quantity of 20-50 mgs per day.
According to Dr. Lugasi and colleagues studies, the
average flavonoid intake in our country is:

children:

19,5 26,6 mg/person

adults:

18,8 28,9 mg/person

Personal consumption

children:

0-179,3 mg,

adults:

0,5-309,7 mg

CONCLUSION
Flavonoids are required substances
from plant kingdom through
animals to human, but their type
and
concentrations
are
very
determined for healthy life.

THANK YOU FOR YOUR

ATTENTION!