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, flavan-
3-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
proantocianidin
other flavonoids 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-γ-pyron stucture are
considered as flavonoids by certain researchers.
These molecules are anthoxantines.

benzo-γ-pyron γ-pyron
chromon
 BIOCHEMICAL PATHWAY
SPECIAL FLAVON OF THE FORMATION OF
DERIVATIVES ROTENONE

• cumaroflavones
• isocumaroflavon
• furanoflavonoids
• biflavones
• coumestan derivatives
• rotenoids

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-γ-pyron

High concentration of
isoflavone quercetin in in vitro
3-phenyl-benzo-γ-pyron experiments causes
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

• 3’, 4’- dihydroxy configuration

Conditions of chelating property: • 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, and their
metabolites arise on intestinal absorption.

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 transduction

radicals in small concentrations • in MMP-ase activity in extra-
may cause apoptosis, and in large cellular space in tumour
quantities necrosis.
 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 15-
lipoxygenase activity.
 FLAVONOIDS AND SIGNAL TRANSDUCTION

The polyphenol like compounds inhibit signal transduction pathways, the TNFα–mediated
activation of NF-κB pathway, partly through the inhibition of IκB kinase and IL-1 β
activated NF-κB pathway, which is a partly distinct route. NF-κB 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.
Direct and indirect
inhibitory actions of
flavonoids within ERK1/2
and Akt/PKB pathways
could initiate cell death,
whereas inhibitory actions
NF-κB, JNK and p53 signaling proteins within JNK pathways are
play an important role in apoptotic more likely to be
death and free radicals and metals are protective.
very important mediators in the [Agullo 1997, Gamet-Payrastre
apoptotic process as well. 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!