secondary metabolites derived from shikimic acid (phenyl … · secondary metabolites derived from...

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


Cleavage of the C3 side chain leads to manyphenyl-C1 compounds.

Phenyl-C1

C C C C

b-Oxidation


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).


DAHP


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.


Chorismic acid

NAD+

- H2O

- CO2

- CO2


Phenylalanine Ammonia Lyase (PAL)

Tyrosine Ammonia Lyase (TAL)


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 Dr. Solomon Derese 13

Lactone formation

Lactone formation

Biosynthesis of Coumarins

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


Biosynthesis of Lignans


Radical pairing A + D;B + D; D + D, etcyield different typesof lignans.


D

D


Secondary metabolites derived from mixed biosynthetic origin (The flavonoids).


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.


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.


O

OFrom shikimic acid pathwayFrom Polykeide

pathway


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


Isoflavonoids


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


4',7-Dihydroxy-6-methoxyisoflavone

7-Hydroxy-3-(4-hydroxyphenyl)-6-methoxy-4H-chromen-4-one

IUPAC Name

Semisystematic Name


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


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).


OO O O

Tetraketide intermediate

SCoA

HO

O

OH

O

O

O

SCoA


The intermediate then folds andcondenses further to give achalcone. This reaction is the firstcommitted step in flavonoidbiosynthesis and is also catalyzedby chalcone synthase (CHS).


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.


FlavanoneSCH 308 36Dr. Solomon Derese

Flavone

These flavanones are the precursors for theconstruction of 5-deoxyflavonoid and 5-hydroxyflavonoid skeletons.

NADPH, O2

-H2O


1,2-aryl migration

H2O-

Isoflavone

NADPH


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+


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:


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


AnthocyaninFlower Pigments


Anthocyanin Leaf Pigments

Autumn Leaves

In Spring and Summerchlorophyll (green)masksthe anthocyanin colors.


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


Sun flower

(Compositae)

O

O

OH

HO

Chrysin

O

O

OH

HO

Quercetin

OH

OH

OH

FLAVONESSCH 308 45Dr. Solomon Derese

Anthocyanin


Knifofia

ANTHRAQUINONES


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


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.


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.


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


V) PhenylalanineIV) Tyrosine

H2N

OHOHO

tyrosine

N O

OH

nicotinic acid

VI) Nicotinic acid

NH2

O OH

phenylalanine


Decarboxylation


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


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


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


N O

NADPH

N OHO

CoAS

O

ON

Tropinone

N

CO2Me

O

O


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


NH

Tryptamine

NH2

OO

O

O Glucose

O H

Secoganin

NH

NH

OO

O

O Glucose

Strictosidine


HONH2

OH

OL-tyrosine


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


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


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


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


N

NH2

O

Nicotinamide

N

O

O

Tigonelline

N

NH

Nicotine

N

NH

H

NornicotineN

NH

H

Anabasine

Ornithine

Lysine


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


NH From L-lysine

N

H

H

H

NADP

Nicotinic acidN

H

N

HH

N

N

HH

Anabasine


N

Nicotinic acid

1,2-Dihydropyridine

H

Enamine-Imine

tautomerizationN

1,4-Dihydropyridine

N

N

HH

Anatabine

N

H

N

H


secondary metabolites derived from shikimic acid (phenyl … · secondary metabolites derived from...

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