Download Slide 1

CHEM-705
Biosynthesis of Natural Products
Set C
February - 2014
1
CHEM-705
Biosynthesis of Natural Products
Set C
Eighth-Twelveth Lectures
Prof. Dr. Shaheen Faizi
2014
2
ALLAH is He “Who has made perfect every
thing he has created.”
(32:8)
“Our Lord is He Who gave unto everything
its proper form and then guided it to its
proper functions.”
(20:51)
3
The Biosynthesis of
Shikimate metabolites
4
Glycolysis
OH
OH
CO2
hv
H2O
OH
O
OH
O
Hexokinase
HO
OH
PO
PO
O
OH
6
OH
Pentose phosphate cycle
OH
OH
glucose 6P
OH
D-glucose
erythrose-4P
Aldolase
COOH
OHC
OH
glycine
CO2H
NH2
Cinnamic acids
3
PO
glyceraldehyde 3-P
Flavonoids
COOH
HO
HO
COOH
HS
HOOC
NH2
OH
L-serine
NH2
L-cysteine
3
3-phospho
glyceric acid
PO
COOH
OH
OH
Shikimic acid
Lignans,
Lignins
Aromatic amino acids
HOOC
OP
Alkaloids
NH2
L-valine
Phosphoenolypruvate
(PEP)
pyruvate kinase
COOH
HOOC
NH2
O
Terpenes, sterols
L-alanine
pyruvic acid
COOH
Mevalonic acid
Acetic acid
NH2
L-leucine
CoAS
Fattyacids, Lipids,
Prostaglandins,
Thromboxanes,
Leukotrienes
O
C
Acetyl-CoA
COOH
HOOC
NH2
L-aspartic acid
S
H2N
L-methionine
Krebs cycle
HOOC
COOH
O
oxaloacetic acid
H2N
H
L-Lysine
Alkaloids
NH2
COOH
COOH HOOC
HOOC
COOH
NH2
O
2-oxoglutaric acid
L-glutamic acid
NH
O
COOH
H2N
N
H
L-arginine
C OH
H2N
NH2
NH2
L-ornithine
5
Primary Metabolism
Alkaloids
S
CO2H
H3C
X
NH2
L Methionin
SCoA
(X = O, N, C)
CH3
C1
COOH
SCoA
C
O
C2
O
malonyl-CoA
acetyl-CoA
C
COOH
NH2
L Phenyldanine
C6C2
COOH
C6C3
NH2
L Tyr
HO
L Phe
L Tyr
N
C6C1
C6C2N
CO2H
NH2
N
L Trp H
H2N
N
N
H
Indd. C2N
COOH
N
L Orn
HN2
NH2
C4N
N
C 5N
N
COOH
N
NH2
L Lys
6
Shikimic acid Metabolites
Pathway of aromatic amino acid metabolism in palnts and micro-organisms is now
universally reffered to as shikimate pathway
Shikimate pathway
Isoprenoid quinone (vitamin K1 and K2)
coenzyme Q, plant phenols
(cinnamic acids, lignans, lignins, etc.)
Chorismate (9)

COOH
OH
H NH+3
L-phenylalanine (10)
HO


CO2
COOH
+
H NH2
COOH
NH2
H
N
H
L-tyrosine (11)
NH2
COOH
L-tryptophan (12)
and the folate co-enzymes
Alkaloids
Indole Alkaloids
10, 11, and 12 are protein--amino acids
7
(PEP) Phosphoenol pyruvate (2)
Glucose
Glycolysis
POCH2 H
D-Glucose
HO
Pentose phosphate cycle
OH

COO
(PEP) (2)
OP CH2
PEP (2)
stereo specific
aldol reaction
Erythrose-4- phospate (1)

HO CO2
H
H 21
O
OH
OH
H
cis elimination
of water
O
HO CO2H
7 6
POH2C
OH
DAHP (3)
3'-deoxy-Darabinohep tulosonic
acid 7-phosphate
Reduction
OH
4
5
OH

CO2
OH
3-Dehydroquinate (5)
1

CO2
2
HOO 3
NADPH
H
HO

CO2
OH
OH
Shikimate (7)
3-Dehydroshikimate (6)
-2H
NADH
COOH
COOH
HO
OH
OH
quinic acid
HO
OH
protocatechuic acid
HO
OH
OH
gallic acid


CO2
CO2
1
Phosphorylation
H
2
2
6
7
CH2
H CH2 1,4 conjugate eliminaion
3
3
5
4


Pyruvate
(2)
OH
O CO2 of phosphoric acid
PO
O CO2
PO
OH
OH
OH

CO2
1
(PEP)
Phosphoenol
Shikimate 3-phosphate
8
5-Enolpyruvyl shikimate 3-phosphate (8) Chorismate (9)
Shikimic pathway
CO2
POCH2 H
D-Glucose
pentose
phosphate
cycle
Glucose
sis
ly
o
yc
Gl
HO
O
P O
OH
Erythrose 4-phosphate (1)
CH2
Phosphoenol pyruvate (2)
(PEP)
1
(1) + (2)
CO2
DAHP- (3-deoxy-D-arabinoheptulosonic acid, 7-phosphatesyuthetase
2
O
HO
synthetase (Enzyme)
Aldol condensation (stereospecific)
P
4
7
POH2C
6
5
OH
H
OH
3-deoxy-D-arabinoheptulosonic
acid 7-phosphate (3) (DAHP)
O
P = phosphate =
3
O
O
Mechanism
1
Phospoenol pyruvate
CO2
PEP (2)
Enzyme
Enzyme
CO2

3
O 2
O2C
OP Stereospecific
OP
OH
4
Reaction
O
O
5
 si
6
O
O
OH
O
CH2
OHPOCH2
re Aldol
H
condensation
OH
H
OH
EnzymePOCH
2
DAHP (3)
OH
7
5 4
6
POH2C
O H OH
+
HO
OH
Enzyme
OP
Hz
HE
COOH
si
(2)
H
O
HOH2C(CHOH)2
O
OH
re
(1)
9
1 
CO2
O
2
3-Dehydroquinate synthetase
3
OH
5
6
1
2
H
(NAD+) Nicotinamide adenine dinucleotide
(coenzyme for oxidation)
OH
O
4
7
POH2C

CO2
HO
H
6
5
3
4
OH

CO2
OH
*
DAHP (3)
H
OH
1
2
3-Dehdroquinate (5)
6
3-dehydroquinate dehydrase
5
3
(isolated and characterised)
O
4
OH
3-Dehydroshikimate (6)
OH
Mechanism (5
6) (cis elimination of H2O
NH2
O
(electropositive gp)
X+

CO2
6
2
3
1
OH
4
5
OH 3-dehydroquinate
(5) (boat or skew
H
HO(basic
B:
boat conformation)
gp)
N
+X

CO2
6
2
3
OH
4
1
OH
Schiff base
5
OHH
B:
Enzyme (3dehydroquinate
dehydrase)
4
HO
HO
+
X

CO2
+
X
N
6
2
3
CO2
4
HO
N
1
3
5
H OH
+B
Enzyme O
3
6
5
OH B:
OH

CO2
(enolate type anion)
HO
1
2

CO2
4
6
2
1
5
(6)
+
Enzyme
OH
O
OH
OH
3-Dehydroshikimate (6)
10


CO2
CO2
3-dehydroshikimate
reductase (enzyme isolated and
characterized)
OH
HO
(NADPH)
O
OH

CO2
PO
6
3
Phosphoenol pyruvate
(PEP)
OH
CO2
Shikimate 3-phosphate (7)
HO
CH2

5-Enolpyruvyl shikimate 3-phosphate (8)
A

CO2
1
3
5
CO2
OH
H

H

O
CO2
6
CH2
Enzyme
CO2
2
(ATP)
OH
PO
Mechanism for the formation of 8
OH
5
4
OH
4
Shikimate kinase
(enzyme isolated and
characterized)
OH
Shikimate (7)
Isolated in 1885 from
aniseed fruit CO
2
5-enolpyruvylshikimate 3-phosphate
synthetase (enzyme isolated and
characterized)
3-Dehydro shikimate (6)
PO
1
H
H
OH

PO (PEP) CO2 PO
OP
OH
6
2

O
1
H

CO2
3
HR
HS
5
4
PO
OH
1,4 conjugate
elimination of
phosphoric acid
CO2

H
H
CH2

PO
O
OH
OP
O
CO2
2
chorismate
synthetase
(enzyme
isolated
charactered)
HS
H
CO
(8)
Shikimate 3-phosphate (7)
P = phosphate
CO2

O
OH
Chorismrate (9)
CO2
11
Mechanism 8
9
(overall trans stereochemistry of elimination of phosphonic acid)
CH2
Enzyme
OP X
5
3
1
2
HO
4
O HR
6
CO2
CH2

CO2
OP
HS
O2 C
Enzyme
5
O
X
2
HO
4
3
CO2
1
6
5-enolpyruvyl shikimate
3-phosphate (8)
HR
H+
A two-step 'X group mechanism' was postulated in
order to account for the overall trans stereochemsitry
of the elimiation process
CO2
1
HS
2
PO = Phosphate
CH2
5
3
4
O
OH
CO2
Chorismate
(9)
+
Enzyme
CO2-
Shikimate Kinase
HO
OH
( Enzyme )
Complex
OH
Shikimate (7)
( Substrate )
This complex was analysed by multinuclear multidimensional NMR spectroscopy.
Total assignment of resonances has been made and the assignment data have been
deposited in the BIO Mag Res Bank database
Nat. Prod. Report 20, 119-136(2003)
12
O
CO2
CH2
CO2
H2N
L-Glutamine
4
O
OH
CO2
CH2
NH3
4
CO2 amination using ammonia
(generated from glutamine as nucleophile)
NH2
Enzyme
O
CO2
4 - Amino-4-deoxychorismate
Chorismate
CO2
O
4 - amino-4- deoxychorismate lyase
+
( ADCL )
CO2
NH2
4 - Aminobenzoate
(part of folic acid)
Pyruvate
13
COO
COOH
p-Hydroxy
benzoic acid
H
NH3+
N
H
(13)
CO2
L-Tryptophan(12)
COOH
H
OH
NH3+
HO
CH2
L-Tryosine (11)
COOH
CO2
CH2
O
H
OH
p-Amino
benzoic acid (14)
(folate coenzyme)
NH3+
L-Phenylalanine (10)
Chorismate (9)
Isoprenoid quinones
(vitamin K1 & K2, coenzyme Q)
NH2
Biosynthesis of the Aromatic Amino-Acids
(10, 11)
O
CO2
CO2
CO2
O

H
O
CO2
H2O
1
2
6
Trans amination
prephenate
dehydratase
te
isma
Chorutase
m
CO2
CH2
OH
4
Phenyl
pyruvic acid (26)
Prephenate (25)
3
5
4
OH
Chorismate
(9)
O
O
CO2
ch
o
mu risma
tas te
e
NH3
C
O
L-Phenylalanine (10)
CO2
CO2
CO2
H
O

O2C
Trans amination
1
2
6
prephenate
dehydrogenase
CO2
5
4
NH3
4
3
H
OH
Prephenate (25)
OH
p-Hydroxy
phenylpyruvic acid
OH
L-Tyrosine (11)
14
Rearrangement of chorismic acid to prephenic acid
(Ortho-Claisen type rearrangement)
1
H
COOH
6
C
2
4
5
HO
3
Inversion of
conformation HOOC
of ring
H
O
H
O
COOH
6
1
H
5
COOH

(9a) chair type conformation of interacting
 system
2
3
4
OH
(9b)
O
O
O
C
chorismate mutase
enzyme
CO2
O
C
CH2
1
4
5
HO
OH
Prephenate (25)
COOH
6
3
COOH
2
Prephenic acid (25)
15
O
C
O
OH
H
O
O
O O
COOH
H
C
O
CO2
H
C
C
Claisen
rearrangement
NAD+
oxidation
CO2H
O
NH2
NH2
H
NH2
4-Amino-4-deoxychorismic acid
Imine
CO2H
CO2H
O
CO2
COOH
NH2
Transamination
PLP
O
HO
H
N
CHCl2CSCoA
C
O
Hydroxylation
N-acylation
C
H
Cl
NH2
NH2
L-p-Amino phenylalanine
(L-PAPA)
Cl
NH2
CH2OH
HO
H
N
Reduction
ofacid
C
Oxidation
ofNH2
CH
Cl
PLP =
Pyridoxal 5'Phosphate
O
Cl
NO2
Chloromphenicol
(chloromycetin)
16
Biosynthesis of Tryptophan
O
COO
CO2
COO
H2N
NH3+
H
HO
O
Alkaloids
L-Glutamine
CH2
NH3
anthranilate synthetase
(removed of enolpyruvyl
gp as pyruvate
CO2
Anthranilate (35)
Chorismate (9)
CO2
CO2
H
H
NH3
2
H
1
5
3
CH2OP
OH
OH
4
O
Phosphoribosyl
transferase
HO
H
H
OH
OH
CH2OP
O
5-Phosphoriboxyl
pyrophosphate (36)
(35)
H
NH
H
PPO
amino aldose
(lablie amino sugar)
H
PPO
Amadori type
rearrangment
CH2OP
OH
CO2
H
Enzyme
N
H
NH
Indolglycerol phosphate(IGP) (38)
HO
H
CH2OP
L-Tryptophan
Pyridoxal phosphate
synthetase
(,2)
H3N+
H
Deoxyribulose
Amadori
comound (37)
(amino ketose)
CO2
H
CO2
HOCH2
H
O
CHO
L-Serine
OP
O
NH3
HO
CH2
P
O
OH
OH
N
H
L-Tryptophan (12)
Me
N
Pyridoxal phosphate coenzyme
17
Mechanisms
6
5
CO2
HO
CO2
C
1
COOH
H2N
2
4
H
O

3
O
H2N
H
HO
L-glutamine
anthranilate
synthetase
CH2
O
CO2
C
Chorismate (9)
NH2
O
CO2
HH

H CO2
H
N
O
H
N
O
O
CH2
O
CH3
H
OH
OH
Cyclic intermediate
COOH
H2O
CH2
H
N
CO2
COOH
O
O
O
NH3+
NH2
CH3
C COH
 pyruvic acid
O
H2O
CH3
Anthranilic acid
Anthranilate
alkaloids
18
Amadori Rearrangement (The Carbolydrates Chem. & Biochem. Sec. Ed 1980)
NH2
CH2OH
O
H
H
OH H
OH
H
OH
H
OH
D-Glucose
CH3
+ H2O+H+
heat 30 mint.
H+
H2C NH
CH2OH
O
H
H
H
OH H
NH
OH
H
OH
Labile product
Glycosyl amine
(Amino sugar)
CH3
CH3
O
HOCH
HC OH
CH OH
CH2 OH
Stable product
(crystalline)
(Amadori compound)
19
chorismate
(9)
COOH
H
H
2
H
3
NH2
5
CH2OP
OH HO 4
PPO
O
Phosphoribosyl
transferase
+
1
H
5-Phosphoribosyl
1-pyrophosphate (36)
Anthranilic acid (35)
CO2
CO2
H+
H
H 5
NH 2
3 CH2OP Amadori
rearrangement
HO
4
1 OH
O
H
H
H+
(Amino sugar)
(Glycosyl amine)
CO2
H
+N
H
H
NH
CH2OP
HO
OH
+
HO
H
H
CO2
Enzyme
H
H
X
CH2OP HX
OH HO
HO H
H
Immomium compound
N
H
H
OH
C
H
CH2OP
HO
HO
H
Enaminol
CO2
H
N
HO
H
CH2OP
O
H
OH
Deoxyribulose (37)
(Amadori compound)
20
CO2
O
NH
O
H
HO
OH OH
C
H
CH2OP
CH2OP
OH
H
H O
Deoxyribulose (37)
R
H
OH
N
H+
HO
OH
H
CH2OP
CO2
OH
H
CO2
NH3
H
N
H
H
L-tryptophan
CH2OP synthetase ,
(enzyme)
OH
Pyridoxal
phosphate
L-serine
H
HO
H
H2O
N
H
L-Tryptophan (12)
N
H
Indolglycerolphosphate (IGP) (38)
Enzyme
Mechanism
O
C
L-tryptophan synthetase
O
Enzyme
H
H2
C
HO
P
OH
O
NH2
Apo-enzyme
H
Me
O
PO3
HC
H
NH2
N CH
H2C
OH
+
H2N
H2C
N
NH2R
Serine
OH
Enzyme
N
Pyridoxal phosphate
(co-enzyme)
O
O3 P
HC
H2C
COOH
N
H
Me
Imine
(Holoenzyme)
OH
CO2
HOCH2
Serine
N
H
Me
Imine
21
H
O
Enzyme
H2C
HO
Enzyme
C
HO
H2C
C
C
N
O
OH
C
N
PO3
O
OH
HC
H2C
PO3
H+
O
OH
N
H+
H2C
N
H
OH
H2O
Enzyme
OPO3
Me
Imine
O
H2C
OH
Me
Imine
C
HC
C
H
OH
CH2OP
OH
HO
H
N
O
HC
H2C
H2C
OH
N
H
N
H
Indolglycerol
phosphate (38)
(IGP)
Me
(A)
H
C
C
OH
Enzyme
N
OPO3
HC
H2C
OH
N
H
CH2OP
OH
Me
(A)
HO
H
CH2
O
C
C
OH
N
N
H
Serine residue
HC
O3POCH2
OH
Enzyme
N
H
Me
22
H
H
CH2OP
OH
H
O
C
C
O
H
CH2
O
OH
+
CH2
H
C
C
N
H
O
N
N
H+
N
OH
Enzyme O3POCH2
CHOH
OH
OH2
OH
Enzyme
CH2OH
Me
N
H
D-glyceraldelyde
N
H
C
O3POCH2
CH
HC
H
Me
O
CH
Serine COOH
residue
H
H2C
NH2
HO
O
CH2 O P
OH
OH
+
Me
N
Pyridoxal
phosphate
(coenzyme)
N
H
+
Enzyme
(apo enzyme)
L-Tryptophan
(12)
Plants
Indole Alkaloids
Metabolism in higher
organisms and micro-organisms
NH2
N
H
HO
Indole
5
degradation
N
H
Serotinin
Pyruvate + NH3
23
CH2OP
OH
H
H
O
H
H
 subunit of enzyme complex
+
L-tryptophan synthetase
N
H
N
H
IGP (38)
CH2OP
OH
C
H
O
not a true intermediate D-glyceraldehyde
H3N+
+
HOH2C
N
H
H
CO2
Indole
2
(Sub-unit of enzyme compound)
Pyridoxal
phosphate
L-serine
CO2
H
NH3
N
H
L-Tryptophan
Isotopic tracer and
Enzymatic studies
24
CO2
NH3+
Anthranilate
type II
DAHP
isozymes
HO
O
N
O
Aurachin A
(e-transport inhibitors)
Nat. Prod. Report 20, 119-136 (2003)
25
Biosynthesis of pyrrolnitrin by bacteria
Cl
NO2
Cl
N
H
Pyrrolnitrin (1)
Pyrrolnitrin (1) is an antifungal tryptophan derived metabolite produced by a number of pseudomonads. It is a phenylpyrrole
derivative and has high antibiotic activity against dermatopytic fungi, especially against members of the genus Trichophyton
and was soon marketed in Japan under the name PYRO-ACE for the treatment of superficial dermatophytic infections.
A) Feeding experiments and ioslation of intermediates
COOH
8
4
COOH
NH2
COOH
3
5
NH2
6
1
7
Anthranilic acid (2)
DL-phenylalanine (3)
2
NH2
N
H
Tryptophan (4)
Addition of 2 or 3 to Pseudomonas aureofaciens inhibited the production of 1, whereas addition of (4) resulted in an
increase of the production of 1. Feeding experiments using DL-tryptophan 3-14C confirmed that 1 is derived from 4.
B) Enzymology and molecular genetics
a) Isolatin of enzymes
b) Characterising and cloning of the biosynthetic gene
c) Sequencing of genes
26
CO2H
CO2H
tryptophan 
NH2
NH2
7-halogenase
[O], NADH, FAD
N
H
7
N
H
O
Epoxide
(intermediate)
Tryptophan (4)
CO2H
ClCO2H
NH2
H2O
NH2
N
H
Cl
7
monodechloroamino
pyrrolnitrin synthase
N
H
NH2
8
Cl
(6)
7
HO
7-Chlorotryptophan (5)
H
3-halogenase
Cl-, NADH, FAD
monodechloroaminopyrrolnitrin
N
H
Cl
Cl
Cl
NH
aminopyrrolnitrin
oxygenase
NH2
N
H
NO2
Nat. Prod. Report 17, 157 (2000)
Nat. Prod. Report 20, 119 (2003)
Cl
(7)
Cl
Pyrrolnitrin (1)
27
CO2H
H
NH2
N
H
L-Tryptophan
cytochrome P450 enzyme
(isolated and characterized)
3
N
OH
Indole-3-acetaldoxime
N
H
N
3
N
H
S  Glucose
Indole-3-acetonitrile
NOSO3
N
H
3
N
H
Indole-3-acetic acid
(IAA)
COOH
indolyl-3-methyl
glucosinolate
Isothiocyante
Nat. Prod. Report. 20, 119 (2003)
28
CO2
Biosyn. of m-carboxy-substituted aromatic amino-acids (30-33) (non-protenic)
CO2
CO2
O
OH
H
OH
CH2

O2C
CH2
+H2O
H2O
CO2
O
CO2
O
CO2
O
OH
Isochorismic acid (28)
Chorismic acid (9)
OH
OH
Prephenate (25)
(27)
CO2
Ortho Claisen rearrangement
CO2
H
NHMe
OH
H
H
Adrenaline
(29)
O
OH
CO2
CO2
H
NH3+
HO
CO2
OH
L-Tyrosine (11)
OH
hydroxylase
Alkaloids
OH
CO2
H
O

NH3+
NH3
O2C
H
(30)

NH3
O2C
H
CO2
NH
O
(31)
melanin pigment
CO2
H3N
CO2
(32)
CO2
OH
L-Dopa (34)
3',4'-Dihydroxy L-phenylalanine
(non-protein amino acid)
H
H
4'
HO
OH
H3N
3'
n
(33)
(30-33) These acids are members of a large group
of amino acids found in higher plants that are not
normally encountered as constituents of proteins
29
Aryl hydroxylation and NIH shift
R
R
R
H
Hydroxylase
Oxygen atom
type species
+
H
H
Arene oxide
H
R
O
*
H
O
H
R
R
hydroxylase
H
H*
O
*
H
HO
OH
OH
NIH shift : J. Nat. Prod. 63, 713 (2000)
H
COO
H
L-Tyrosine

NH3
HO

NH2
H
L-dopadecarboxylase
CO2
HO
HO
OH
Dopamine
L-Dopa
HO
HO
dopamine
-hydroxylase
HO
H

HO
NH2

L-methionine
N-methyltransferase
H
HO
NHM
HO
Adrenaline
(catechol amine)
30
Methylation of RNH2 or ROH with methionine
NH2
N
N
N
O
N
N
H2C
O
PPP OH2C
H3C
OH
OH
S+
HO
CH2
HO
H3C
RNH2
(Amine)
(ATP)
S:
HC
H2C
NH2
COOH
CH2
HC
CH2
S-adenosyl methionine
(SAM)
NH2
COOH
(Mithionine)
Transfer of methyl group
N
O
CH2
S
OH
+
HO
CH2
RNH CH3
(Methyl amine)
CH2
CHNH2
COOH
S-adenosylhomo cysteine
31
HR
Metabolism of L-phenylalanine
HR
Hs
2
3
CO2-
1
CO2-
L-Phenylalanine
amino lyase (PAL)
NH3
H
hydroxylase
H
NH3
( anti elimiation )
L-phenylalanine
Trans-Cinnamate
( Cinnamic acid )
CO2
hydroxylase
HO
NIH shift
(Coumarte)
(p-Coumaric acid)
CO2
HO
HO
Caffeate
(Caffeic acid)
H3CO
Methionine
CO2
SAM (ATP)
hydroxylase
NIH shift
HO
NIH shift
SAM
Methionine
(ATP)
Ferulate
(Ferulic acid)
CO2
MeO
HO
OMe

COOH
COOH
Sinapate
(Sinapic acid)
COOH

OH
Trans cinnamic acid
H
Nat. Prod. Report 173, (1994)
Benzoic acid
H
CO2
COOH
CO2H
NH3
HO
H
Tyrosine
HO
HO
HO
COOH HO
COOH
Similar proposals have also been
advanced to account for the biogenesis of related aldelydes, alcohols and the phenylacetic acids.
HO
HO
32
COOH
+
CH2-OH
COOH
CH2
-
H+
H
NH2
Enzyme
Enzyme
Enzyme
-H2O
L-Phenylalanine
CH3
Cinnamic acid
E
Enzyme
me
nzy

CO2H
H
+
OH
Enzyme
H2O
Enzyme
COOH
H-O
CH2OH
Eugenol
HO
reverse aldol reaction
O
OH
O
H
C
x2
Lignan
Polymerisation
xn
C
OH
NAD+
Lignin
33
HO
OH
CO2H
Cytochrome
P-450
H2N
HO
CO2H
NH
HO
OH
Tyrosine
H
CO2H
Enzyme
N
HO
N
OH
HO
OH
4 - Hydroxyphenyl acetaldoxime
OGluc
H
C
HOOC
HOOC
N
HO
N
HO
Triglochinin
C
Natural Product Report 20, 119
(2003)
N
HO
4-Hydroxyphenylacetonitrile
GlucO
OH
C
HO
N
H
C
Enzyme
N
HO
Taxiphylin
34
O
Isoprenoid Quinones
Lipid soluble quinones
MeO
Me
3
5,6-Dimethoxy 3-methyl-2-trans.polyprenyl -1,4benzoquinones ( Coenzyme Q )
( n = 1-12 )
H
5
2
6
1
MeO
O
Me
n
Polyprenyl
side chain
Ubiquinones ( Coenzyme Q ) are localized in mitochondria of plants
and animals
O
Me
Vatamin
K- 1
H
Me
O
L-Tyrosine
n
L-Tryptophane
I
O
I
+
NH3
CO2-
I
HO
I
COOH
H
Me
Thyroxine
O
O
N
O
OH
COOH
COOH
OH
NH2
Me
OH
O
Lawsone
O
OH
Pseudopurpurin
(anthraquinone)
O
Actinocin
( antibiotic)
(52)
35
Nat. Prod. Report 17, 269 (2000)
O
O
BzCNH
13
O
OH
HR
Hs
Taxol
15
Phenylalanine
aminomutase
NH2

3 2
H*
1
COOH
 - Phenyl
alanine
15
NH2
HR
Hs
 
H*
COOH
 - Phenylalanine
Enzyme Benzoylation
Hydroxylation
O
O
BzCNH


13
O
OH
Phenylisoserine side
chain of taxol
36
COOH
COOH
Enzyme
OH
Cinnamic acid
Coumarin
O
O
Lignans
O
Pinoresinol
Podophyllotoxin
O
HO
OCH3
O
OMe
C
N
CH3
Herclavine
Acetate pathway
Phenols
Meta-Substitution
pattern of OH
Phytochemistry, 71 1808-1824 (2010)
Shikimate pathway
Phenols
p-hydroxy
o-hydroxy or
1,2,3-trihydroxy substitution
pattern of OH
37
1
L. M. Poduct and D. H. Sherman, Diversity of P450 enzymes in the biosynthesis of natural products, Nat. Prod. Rep., 2012, 29,
1251-1266.
2
N. C. Veitch and. R. J. Grayer, Flavonoids and their glycosides, including anthocyanins, Nat. Prod. Rep., 2011, 28, 1626-1695.
3
R. Tsao, Chemistry and biochemistry of dietary polyphenols, Nutrie., 2010, 2, 1231-1246.
4
K. Yoshida, M. Mori and T. Kondo, Blue flower color development by anthocyanins: from chemical structure to cell
physiology, Nat. Prod. Rep., 2009, 26, 884-915.
5
N. Erkan, Huseyin Cetin, E. Ayranci, Antioxidant activities of Sideritis congesta Davis et Huber-morath and Sideritis arguta
boiss et heldr: Identification of free flavonoids and cinamic acid derivatives, Food Res. Inter., 2011, 44, 297-303.
6
K. Nagy, K. Redeuil, G. Williamson, S. Rezzi, F. Dionisi, K. Longet, F. Destaillats, M. Renouf, First identification of
dimethoxycinnamic acids in human plasma after coffee intake by liquid chromatography-mass spectrometry, J. Chromatog.,
2011, 1218, 491-497.
7
E. S.-Rodriquez, D. A. Moreno, F. Ferreres, M. D. M. R.-Wilhelmi, J. M. Ruiz, Differential responses of five cherry tomato
varieties to water stress: changes on phenolic metabolites and related enzymes, Phytochem., 2011, 72, 723-729.
8
X. Dong, T. Liu, J. Yan, P. Wu, J. Chen, Y. Hu, Synthesis, biological evaluation and quantitative structure-activities relationship
of flavonoids as vasorelaxant agents, Bioorg. Med. Chem., 2009, 17, 716-726.
9
S. Protti, A. Mezzetti, C. Lapouge and J.-P. Cornard, Photochemistry of metal complexes of 3-hydroxyflavone: towards a better
understanding of the influence of solar light on the metal-soil organic matter interactions, Photochem. Photobiol. Sci., 2008, 7,
109-119.
10
A. R. Knaggs, The biosynthesis of shikimate metabolites, Nat. Prod. Rep., 2003, 20, 119-136.
A. R. Knaggs, The biosynthesis of shikimate metabolites, Nat. Prod. Rep., 2001, 18, 334-355.
A. R. Knaggs, The biosynthesis of shikimate metabolites, Nat. Prod. Rep., 2000, 17, 269-292.
A. R. Knaggs, The biosynthesis of shikimate metabolites, Nat. Prod. Rep., 1999, 16, 525-560.
38
11
Flavonoid Biosynthesis, Nat. Prod. Rep., 2000, 17, 376.
12
L. B. Davin, M. Jourdes, A. M. Patten, K. W. Kim, D. G. Vassao and N. G. Lewis, Processes in allyl/propenyl phenol and
lignin biosynthesis, Nat. Prod. Rep., 2008, 25, 1015-1090.
b
A. Crozier, I. B. Jaganath and M. N. Clifford, Dietary phenolics : chemistry bioavailability and effects on health, Nat. Prod.
Rep., 2009, 26, 1001-1043.
13
N. C. Veitch and R. J. Grayer, Flavonoids and their glycosides, including anthocyannins, Nat. Prod. Rep., 2008, 25, 555-611.
14
S. E. Drewes, S. F. van Vuuren. Antimicrobial acylphloroglucinols and dibenzyloxy flavonoids from flowers of Helichrysum
gymnocomum. Phytochem., 2008, 69, 1745-1749.
15
C. Canela, R. M. Moraesb, F. E. Dayana, D. Ferreira, Molecules of interest podophyllotoxin, Phytochem. 2000, 54, 115-120.
16
P. J. Facchini, Kara L. H. Allanach, L. W. Tari, Plant aromatic L-amino acid decarboxylases: evolution, biochemistry,
regulation, and metabolic engineering applications, Phytochem. 2000, 54, 121-138.
17
P. Manitto, D. Monti, G. Speranza. Evidence for an NIH-shift as the origin of the apparently anomalous distribution of
deuterium in natural cstragole. J. Nat. Prod., 2000, 63, 713-715.
18
J. Schmid and N. Amrhein. Molecular organization of the shikimate pathway in higher plants, Phytochem., 1995, 39, 737-749.
19
Paul M. Dewick. Medicinal natural products, a biosynthetic approach. John Wiley & Sons, 2002.
20
E. Haslam, S. D. Barton, and W. D. Ollis, Comprehensive organic chemistry, Shikimic acid metabolites, volume-5, Biological
Compounds, 1979.
21
Enclopedia of chemical technology. Kirk-Orthmcr. Various Vols.
22
R. Thomas. Biogenetic speculation and biosynthetic advances. Nat. Prod. Rep., 2004, 21, 224-248.
39
23
M. Fullbck, E. Miehalsky. M. Dunkel and R. Preissner. Natural products: sources and databases. Nat. Prod. Rep.,
2006, 23, 347-356.
24
Turnbull, J. Jonathan et al. Figures l and 3 in mechanistic studies on three 2-oxoglutaratc-dependent oxygcnases of
flavonoid biosynthesis: Anthocyanidin synthase, flavonol synthase, and flavanone 3{}-hydroxylase. J. Biol. Chem.,
2004, 279, 1206-1216. http://www.jbc.org/cgi/reprint/279/2/1206
25
Fukusaki, Ei-ichiro et al. Figures 1 and 3 in flower color modulations of Torenia hybrida by downregulation of
chalcone synthase genes with RNA intcrlèrence. J. Biotech. 2004, 111, 229-240.
26
Xie, De-Yu et al. Figures 3 and 2 in role of anthocyanidin reductase, encoded by 13ANYULS in plant flavonoid
biosynthesis. Science, 2003, 299, 396-399.
27
Winkel-Shirley, Brenda. Figure 1 in Flavonoid Biosynthesis. A colorful model for genetics, biochemistry, cell biology,
and biotechnology. Plant Physiol., 2001, 126, 485-493. http://www.plantphysiol.org/gci/content/full/126/2/485
28
Hashim, M. Faisal et al. Figure 2 in reaction mechamism of oxidative rearrangement of flavanone in isoflavone
biosynthesis. FEBS Lett., 1990. 271. 219-222.
29
H.-X. Xu, S. F. Lee, Activity of flavonoids against antibiotic-resistant bacteria, Phyto. Res., 2001, 15, 39-43.
30
T.P. T. Cushnie, A. J. Lamb, Antimicrobial activity of flavonoids, Int. J. Antimicrob. Agents, 2005, 26, 343–356.
31
J. E. Bassard, P. Ullmann, F. Bernier, D. W. Reichhart, Phenolamides: Bridging polyamines to the phenolic
metabolism, Phytochem., 2010, 71, 1808-1824.
32
S. Martens and A. Mithöfer, Flavones and flavone synthases, Phytochem., 2005, 66, 2399-2407.
33
K. H. Pee, and J. M. Ligon, Biosynthesis of pyrrolnitrin and other phenylpyrrole derivatives by bacteria, Nat. Prod.
Rep., 2000, 17, 157-164.
40
41