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Secondary metabolites derived from Shikimic acid (Phenyl propanoids and
Lignans)
SCH 308 1Dr. Solomon Derese
Learning Objectives
• Recognize the role of shikimic acid, chorismic acid
and prephenic acid in biosynthesis.
• Recognize that cinnamic acid derivatives are
precursors to other natural products like lignans
and coumarines.
2SCH 308 Dr. Solomon Derese
The Shikimic Acid Pathway
This pathway (unique to plants) leads to theformation of the aromatic amino acidsphenylalanine and tyrosine and to the formation ofmany other phenyl-C3 compounds(phenylpropanoids).
C C C
Phenylpropanoids
Phenyl-C3
SCH 308 3Dr. Solomon Derese
Cleavage of the C3 side chain leads to manyphenyl-C1 compounds.
Phenyl-C1
C C C C
b-Oxidation
SCH 308 4Dr. Solomon Derese
Biosynthesis of Shikimic Acid
The shikimate pathway begins with thecondensation of PhosphoEnolPyruvate(PEP) and D-erythrose 4-phosphategiving 3-Deoxy-D-Arabino-Heptulosonate-7-Phosphate (DAHP) in areaction catalysed by the enzymephospho-2-dehydro-3-deoxyheptonatealdolase (DAHP synthase).
SCH 308 5Dr. Solomon Derese
DAHP
SCH 308 6Dr. Solomon Derese
SCH 308 7Dr. Solomon Derese
Chorismate is a key Intermediate in theSynthesis of Tryptophan, Phenylalanine, andTyrosine.
Aromatic rings are not readily available in theenvironment, even though the benzene ringis very stable. The branched pathway totryptophan, phenylalanine, and tyrosine,occurring in bacteria, fungi, and plants, is themain biological route of aromatic ringformation.
SCH 308 8Dr. Solomon Derese
Chorismic acid
NAD+
- H2O
- CO2
- CO2
SCH 308 9Dr. Solomon Derese
Phenylalanine Ammonia Lyase (PAL)
Tyrosine Ammonia Lyase (TAL)
SCH 308 10Dr. Solomon Derese
Coumarins
Secondary metabolites with the general formula:
It has a sweet scent, readily recognized as the scentof newly-mown hay.
Coumarins have a C6-C3
skeleton, with an oxygenheterocycle as part of theC3-unit.
Coumarins owe their class name to ‘Coumarou’, thevernacular name of the tonka bean (Dipteryxodorata Willd.,Fabaceae), from which coumarinitself was isolated in 1820.SCH 308 11Dr. Solomon Derese
O OHO
Umbeliferone
O OHO
HO
Aesculetin Herniarin
O OMeO
O OO
Psoralen
O OO
OImperatorin
Examples of Coumarins
SCH 308 12Dr. Solomon Derese
SCH 308 Dr. Solomon Derese 13
Lactone formation
Lactone formation
Biosynthesis of Coumarins
SCH 308 14Dr. Solomon Derese
Lignans
Lignans are a large group of natural productscharacterized by the coupling of two C6C3
units.
Lignans are a class of naturally occurringplant phenols that are derivedbiosynthetically from dimerization ofcinnamic acid.
Definition
SCH 308 15Dr. Solomon Derese
Biosynthesis of Lignans
SCH 308 16Dr. Solomon Derese
Radical pairing A + D;B + D; D + D, etcyield different typesof lignans.
SCH 308 17Dr. Solomon Derese
D
D
SCH 308 18Dr. Solomon Derese
SCH 308 19Dr. Solomon Derese
SCH 308 20Dr. Solomon Derese
SCH 308 21Dr. Solomon Derese
Secondary metabolites derived from mixed biosynthetic origin (The flavonoids).
SCH 308 22Dr. Solomon Derese
The flavonoids comprise a large group ofsecondary metabolites which are derivedfrom sub-units supplied by the acetateand shikimate pathways.
They occur almost exclusively in higherplants and are responsible for much ofthe flavor of food and drink of plantorigin and for the colors of flowers.
SCH 308 23Dr. Solomon Derese
The term “flavonoid” is generally used todescribe a broad collection of naturalproducts that has a C6-C3-C6 (two benzenerings joined by three carbons) carbonframework.
In plants, flavonoids are involved in suchdiverse processes such as UV protection,pigmentation, stimulation of nitrogen-fixingnodules and disease resistance.
SCH 308 24Dr. Solomon Derese
O
OFrom shikimic acid pathwayFrom Polykeide
pathway
SCH 308 25Dr. Solomon Derese
Chalcones
A
B2'
3'
2
3
O
C
Flavan45
A
B2'
3'
2
3
O
C
Flavanone
5O
A
B2'
3'
2
3
O
C
5O
Flavone
Flavonoids
SCH 308 26Dr. Solomon Derese
Isoflavonoids
SCH 308 27Dr. Solomon Derese
O
HO
OH
OH
OH
(S)-5,7-dihydroxy-2-(4-hydroxyphenyl)chroman-4-one
O
HO
OH
OH
OH
345
6
7
8
1'2'
3'
4'
5'6'
2A
B
C
FLAVANONE
4’,5,7-Trihydroxyflavanone
Naming of flavonoids
IUPAC NAME
SEMISYSTEMATIC NAME
SCH 308 28Dr. Solomon Derese
4',7-Dihydroxy-6-methoxyisoflavone
7-Hydroxy-3-(4-hydroxyphenyl)-6-methoxy-4H-chromen-4-one
IUPAC Name
Semisystematic Name
SCH 308 29Dr. Solomon Derese
9-Methoxy-2,3-methylenedioxy-8-prenylpterocarpan
9-Methoxy-8-(3-methylbut-2-enyl)-6a,11a-dihydro-6H-benzofuro[3,2-c][1,3]dioxolo[4,5-g]chromene
IUPAC Name
A B
2
O
C
4 5
OD
6a
11a1
6
78
10OMe
O
O
Semisystematic Name
SCH 308 30Dr. Solomon Derese
Flavonoids are synthesized byextension of p-hydroxycoumaroylCoA with three molecules of malonylCoA in linear manner in order toform a tetraketide intermediate.
This step is catalyzed by the enzymeCHalcone Synthase (CHS).
SCH 308 31Dr. Solomon Derese
OO O O
Tetraketide intermediate
SCoA
HO
O
OH
O
O
O
SCoA
SCH 308 32Dr. Solomon Derese
The intermediate then folds andcondenses further to give achalcone. This reaction is the firstcommitted step in flavonoidbiosynthesis and is also catalyzedby chalcone synthase (CHS).
SCH 308 33Dr. Solomon Derese
O
OH
O
O
O
SCoA
CHSCHS
NADPH, -H2O
LeguminosaeLeguminosae + other plant families.SCH 308 34Dr. Solomon Derese
CHalcone Isomerase (CHI) is the secondenzyme involved in the biosynthesis offlavonoids and it catalyzes thestereospecific intramolecular cyclizationof the chalcones isoliquiritigenin andnaringeninchalcone into the flavanones(2S)-liquiritigenin and (2S)-narigenin,respectively.
SCH 308 35Dr. Solomon Derese
FlavanoneSCH 308 36Dr. Solomon Derese
Flavone
These flavanones are the precursors for theconstruction of 5-deoxyflavonoid and 5-hydroxyflavonoid skeletons.
NADPH, O2
-H2O
SCH 308 37Dr. Solomon Derese
1,2-aryl migration
H2O-
Isoflavone
NADPH
SCH 308 38Dr. Solomon Derese
O
OH
HO
O
H
H
Pterocarpan
O
OOH
HO
[O]
O
OOH
HO
HO
NADPH, H+
O
OOH
HO
HO
O
HOOH
HO
HOH+
SCH 308 39Dr. Solomon Derese
O
O
O
OMe
OMe
HO CH3
Biosynthesis of Rotenoids
O2, NADPH
O
O
O
OMe
OMe
HO CH2
OH
H
O
O
O
OMe
OMe
HOO
O
O
OMe
OMe
HOH
H
Demethylmunduserone
H:
SCH 308 40Dr. Solomon Derese
O
O
O
OMe
OMe
HOH
H
OPP
O
O
O
OMe
OMe
HOH
H
O
O
O
OMe
OMe
H
H
O
Rotenone
Demethylmunduserone
DMAPP
O
O
O
OMe
OMe
H
H
Deguelin
O
Rotenonic acid
SCH 308 41Dr. Solomon Derese
AnthocyaninFlower Pigments
SCH 308 42Dr. Solomon Derese
Anthocyanin Leaf Pigments
Autumn Leaves
In Spring and Summerchlorophyll (green)masksthe anthocyanin colors.
SCH 308 43Dr. Solomon Derese
OH
OH O
OH
O
R
Naringenin (R=H)
OH
OH O
OH
O
OH
R
OH
OH O
OH
OH
OH
R
NADPH
[O]
OH
OH O
OH
OH
OH
R
OH
OH
OH O
OH
OH
R
+
- 2 H2O
O2
pelargonidin (R=H)cyanidin (R=OH)
Anthocyanidins and Anthocyanins
plant flower andleaf pigments
Anthocyanidins cyanidin is bluepelargonidin is pink
Anthocyanins arered, violet or bluePigments, have sugar atC-3.
NADPH
SCH 308 44Dr. Solomon Derese
Sun flower
(Compositae)
O
O
OH
HO
Chrysin
O
O
OH
HO
Quercetin
OH
OH
OH
FLAVONESSCH 308 45Dr. Solomon Derese
Anthocyanin
SCH 308 46Dr. Solomon Derese
Knifofia
ANTHRAQUINONES
SCH 308 47Dr. Solomon Derese
What are Alkaloids?
‘any non-peptidic & non-nucleotide nitrogenoussecondary metabolite’
48SCH 308 Dr. Solomon Derese
Sparteine
N
N
H
H
Lysergicacid
NH
HNO
OH
Quinine
HO
N
H
O
N
N
H Coniine
NicotineN
N
Clavulanic acid
N
O
O
OH
HCO2H
H
Retronecine
N
OHHOH
Strychnine
O
N
O
NH
H
HMorphine
HO
O
HOH
N
SCH 308 49Dr. Solomon Derese
Alkaloids have one or more nitrogen,typically as primary, secondary, or tertiaryamines, and this usually confers basicity tothe alkaloid, facilitating their isolation andpurification since water-soluble salts can beformed in the presence of mineral acids.There also alkaloids which are neutral.
The name alkaloid is in fact derived fromalkali.
SCH 308 50Dr. Solomon Derese
The nitrogen atoms in alkaloids originatefrom an amino acid, and, in general, thecarbon skeleton of the particular aminoacid precursor is largely retained intactin the alkaloid structure, though thecarboxylic acid carbon is often lostthrough decarboxylation.
SCH 308 51Dr. Solomon Derese
The most common amino acids from whichalkaloids are derived from are:
II) LysineI) Ornithine
NH2 NH2O
HO
lysineNH2
NH2
O
HO
ornithine
III) Tryptophan
NH2
NH
O
OH
tryptophan
SCH 308 52Dr. Solomon Derese
V) PhenylalanineIV) Tyrosine
H2N
OHOHO
tyrosine
N O
OH
nicotinic acid
VI) Nicotinic acid
NH2
O OH
phenylalanine
SCH 308 53Dr. Solomon Derese
Decarboxylation
SCH 308 54Dr. Solomon Derese
Ornithine contains both d - and a - aminogroups, and it is the nitrogen from theformer group which is incorporated intoalkaloid structures along with the carbonchain, except for the carboxyl group.
NH2
NH2
O
HO
Ornithine
ad
Non-protein amino acid
SCH 308 55Dr. Solomon Derese
NH2HO
O
NH2
Ornithine
PLP
CO2
NH2H2N
Putrescine
NH2RHN
Alkylation
OXIDATIVE DEAMINATION
HRHNO
N
R
Pyrolidine alkaloids
OXIDATIVEDEAMINATION
R NH2
H2N NH2n
Monoamineoxidase R
O
H
Diamineoxidase
H2N n
O
H
SCH 308 56Dr. Solomon Derese
N
R
Iminium salt
O
SCoA O
O
Malonyl CoA
N
RO
SCoA
[O]
O
SCoA
O
O
N
RO
OSCoA
N
RO
HO
OSCoA
Enz B H
N
OO
CoASR
N
OHO
CoASR
N
OO
CoASR
N
O
R
+ H2O
- CO2
NR
O
SCH 308 57Dr. Solomon Derese
N O
NADPH
N OHO
CoAS
O
ON
Tropinone
N
CO2Me
O
O
SCH 308 58Dr. Solomon Derese
PLP
CO2
OXIDATIVE
DEAMINATIONNH2
CO2H
NH2
Lysine
NH2 NH2
Cadaverine
NH2 O N
Piperideine
H
N
H
O O
SCoA
OH O
SCoAN
HO
O
SCoA
+ H2O
- CO2N
HO
Pelletierine
SAM
N
O
N-Methylpelletierine
N
H
NH
O
N
H
AnaferineSCH 308 59Dr. Solomon Derese
NH2
NH
OOH
Tryptophan
PLP
- CO2 NH
Tryptamine
NH2 2 SAM
NH
N
NH
N
OH
Psilocin
SCH 308 60Dr. Solomon Derese
NH
Tryptamine
NH2
OO
O
O Glucose
O H
Secoganin
NH
NH
OO
O
O Glucose
Strictosidine
SCH 308 61Dr. Solomon Derese
HONH2
OH
OL-tyrosine
SCH 308 62Dr. Solomon Derese
HO
H
OHO
H2N
HO
+ HON
HO
HO
H
HONH
HO
H
HO
SAMHO
NMe
MeO
H[O]HO
NMe
MeO
HHO
MeOHO
SAM
Reticuline
SCH 308 63Dr. Solomon Derese
HONMe
MeO
HHO
MeOReticuline
HONMe
MeO
HHO
MeOBoldine
o,o
HONMe
MeO
H
MeO
o,pOH
NMe
H
MeO
OH
O
O
Bulbocapnine
OXIDATIVE COUPLINGSCH 308 64Dr. Solomon Derese
NH2
O OH
phenylalanine
SCH 308 65Dr. Solomon Derese
NH3
O O
phenylalanine
- NH3 SCoA
O
HSCoA
b-Oxidation SCoA
O
OPyruvate
O
O
O
O
Transamination
O
NH2
SAM
OH
NHMe
OH
NH2
NADPH
NADPH
(–)-ephedrine
(+)-norpseudoephedrine
SAM
OH
NHMe
(+)-pseudoephedrine
(–)-cathinone
KHAT =MIRAA
SCH 308 66Dr. Solomon Derese
Khat (Catha edulis, family Celastraceae;
Arabic: ;قات Somali: Jaad; pronounced
[ˈkæt]; Ge'ez ጫት čāt; miraa in Kiswahili), is
a flowering plant native to tropical East
Africa and the Arabian Peninsula.
Khat contains the alkaloid called cathinone,
an amphetamine-like stimulant which
causes excitement, loss of appetite, and
euphoria. In 1980 the World Health
Organization classified khat as a drug of
abuse that can produce mild to moderate
psychological dependence.SCH 308 67Dr. Solomon Derese
N O
OH
nicotinic acid
SCH 308 68Dr. Solomon Derese
N
NH2
O
Nicotinamide
N
O
O
Tigonelline
N
NH
Nicotine
N
NH
H
NornicotineN
NH
H
Anabasine
Ornithine
Lysine
SCH 308 69Dr. Solomon Derese
N
N
MeH
Nicotine
NNicotinic acid
OH
O
H
H
NADPH
Dihydronicotinicacid
- CO2
N
O
OH
H
H
NH
N
Me
From L-orinthine
N
N
MeH
H
H
H
NADP
SCH 308 70Dr. Solomon Derese
NH From L-lysine
N
H
H
H
NADP
Nicotinic acidN
H
N
HH
N
N
HH
Anabasine
SCH 308 71Dr. Solomon Derese
N
Nicotinic acid
1,2-Dihydropyridine
H
Enamine-Imine
tautomerizationN
1,4-Dihydropyridine
N
N
HH
Anatabine
N
H
N
H
SCH 308 72Dr. Solomon Derese