POLYKETIDES,

ACETOGENINS

ACETYL COENZYME A
A TWO-CARBON BUILDING BLOCK
Acetyl CoA

O
CH3 C S CoA

Can be used like a

molecular Lego piece
.. well , sort of ..

C-C C-C C-C

C
C

C-C C-C C-C

C-C C-C C-C C-C
C-C C-C C-C C-C C-C

C
C
C-C C-C C-C
C-C
C-C
C-C C-C C-C C
C
C-C

CLAISEN CONDENSATION
LIKE THE ALDOL CONDENSATION
BUT WITH ESTERS

REVIEW
REMEMBER
CHEM 353

O
R CH2 C O CH2 CH3
+
O

NaOCH2CH3

-ketoester

R CH2 C CH C O CH2 CH3

CH3CH2OH

R CH2 C O CH2 CH3

Acidic -hydrogens are

removed in strong base
to make an enolate anion
which adds to the C=O
of another molecule.

O
+

CH3 CH2 O H

.. :O :

..
O:
C
..

C OR

C OR

CONCATENATION OF
ACETATE UNITS
O

O
CH3

acetate unit

CH3

S CoA

OH

acetic acid

acetyl CoA

ACETYL CoA UNITS ARE LINKED

BY A CLAISEN-LIKE CONDENSATION
Strong bases are not tolerated
by biological systems. Nature
does these condensations
using malonyl CoA.

H CH2

S CoA

O H
CH2

HOOC Biotin

:B

Differences between an
oxygen ester and a thioester:
Thioesters are more prone
to enolization.
Thioesters are more
reactive.

O
C

WHY THIOESTERS ?

ATP ADP

S CoA
Biotin
Biotin-COOH

O
HOOC CH2

S CoA

malonyl CoA

THE ENZYMES THAT ASSEMBLE ACETYL-CoA UNITS

USE A DECARBOXYLATION OF MALONYL-CoA
A FREE ENOLATE ION IS NEVER FORMED

Enz-B:
CHAIN EXTENDER
malonyl CoA

Enz-B:
H

.. CH

CH3 C

x1

acetyl CoA
STARTER

x2

S CoA

S CoA

- CO2

S CoA

O
C

S CoA

CH3

x3
O

x5 x4

CH2

CH3 C CH2 C CH2 C CH2 C CH2 C SCoA

a polyketide chain

CH2

CH2

.
.

O
O

CH3

O
CH2 C S CoA

THERE ARE TWO CARBONYL GROUPS IN THE 2-UNIT POLYKETIDE CHAIN

EITHER ONE CAN REACT
O

O
H

.. CH

CH3 C

S CoA
CH3

- CO2

S CoA

CH2

LINEAR

BRANCHED

mevalonic acid

CH3
CH2
HO

CH2

OH
C

CH2
CH2 COOH

TERPENES

O
CH3

O
C

CH2

H3C

S CoA

CH2

O
CH2

SCoA

S CoA

CH2
O C

POLYKETIDE CHAINS
SCoA

STEROIDS

ACETOGENINS

THE ASSEMBLY ENZYMES

acetyl - malonyl transferases

O
CH3

acetylCoA
starter

..

cys -SH

CoAS C

-SH

..

C CH
3
O H

OH

-S

malonylCoA
extender

..

O
CH2 C

-SH

..

cys -S

..

-SH

H+

S CoA

-S

more
malonylCoAs

-S

O H

:B
- CO2

CH2
O
O

-SH

- CO2

CH2
O

etc.

:B

O H

:B
- CO2

CH2
O
O

acyl carrier protein

(ACP)
O

CH3 C CH2 C CH2 C CH2 C SCoA

BUILDING THE CHAIN ON A FLEXIBLE LINK

H+

-SH

-S

-SH

ANOTHER MODEL OF THE ENZYME

C CH
3

- CO2

C CH COOH
2

-S-H
-S

O
C CH
2

CH3

transfer
H+

-S

O
C CH
2

CH3

C CH COOH
2

- CO2

-S

Malonyl-CoA

-SH O
-S

C CH C CH
2
2

C CH
2

CH3

-SH

Growing chain

O
CH3

etc

POLYKETIDES
ACCETOGENINS

WE WILL LOOK AT POLYKETIDES FIRST

1 O 2O
3
4
Polyketides are the precursors
O
O

of the class of natural products

called acetogenins

CH3 C CH2 C CH2 C CH2 C SCoA

H2O
hydrolysis

CH3
O
O

CH3
O

- CoASH

CH2

SCoA

internal aldol
condensation

HO CH3 O
OH

CH2
OH

O
O

H
O

enolization
CH3

Orsellinic acid

O
OH

( Lichen spp )

- H2O
dehydration

HO CH3 O
OH
H

HO

OH

an acetogenin
made from acetate units

makes
HO
aromatic
ring

OH

SOME OTHER SIMPLE ACETOGENINS

O

SEnz

internal
Claisen
O

1) enolization
2) SAM

OMe O

MeO

OMe

Eugenone
( oil of cloves )

CH3

SEnz
O

OH
O

(found in Lichen )

ANTHRAQUINONE LAXATIVES
O

HO

OH

OH

SEnz
O

OH

O
MeO

HO

physicon

emodin
OH

Senna
Casacra
Rhubarb
Aloes
Frangula

OH

Penicillium spp
Rhamnus spp
Rumex spp

OH

OH

OH

O
OH
H

rhein
OH

OH

OH
O

aloe-emodin

OH

OH

O Glu

OH

Glu O

OH

cascaroside

GRISEOFULVIN

Penicillium griseofulvin

Anti-fungal, antibiotic for toenail and skin infections absorbed from stomach, concentrated in skin
O

OH

OH

OH

O
SEnz

OMe

SAM

HO

OH

Aldol

OH

MeO

OH

Cl+

O H
..

Claisen
OH

OMe

OH

Cl

OH

O MeO

O
Cl

OH

MeO
Cl

SAM

OMe

[O]

OMe

O MeO

MeO

OMe

reson.

.
MeO

MeO

OH
Cl

FADH2

OMe

O H

O MeO

MeO
Cl

MeO
Cl

griseofulvin

MACROLIDES (LARGE RINGS)

aldol

9 units
O

aromatize
NADPH

SEnz
O

O O

O
O

lactonize

SEnz
O

O HO

..

O
O

NADPH, then
dehydrate

acetylCoA +
8 malonylCoA

OH

NADPH, then
dehydrate,
then FADH2

The various reductions may

be performed during the
chain extension steps rather
than afterward.

macrolide
antibiotic

O
HO

zearalenone
Gibberalla zeae

DIFFERENT STARTERS
AND EXTENDERS
THE METHOD IS NOT RESTRICTED
TO ACETATE UNITS ONLY

MALONAMYL CoA STARTER

O
H2N

O
CH2

malonamylCoA
starter

..

cys -SH

CoAS C

..

-SH

..

C CH C NH
2
2
O H

OH

malonylCoA
extender

..

O
CH2 C

-SH

cys -S

..

-SH

H+

S CoA

etc.

-S

more
malonylCoAs

-SH

:B

O H

- CO2

CH2
O
O

-S

- CO2

CH2
O

-S

:B

:B

O H

- CO2

CH2
O
O

acyl carrier protein

(ACP)
O
H2N

C CH2 C CH2 C CH2 C CH2 C SCoA

TETRACYCLINES
O

Cl HO

SEnz
O
O

NMe2
OH
NH2

NH2

actually starts from

malonamyl CoA which
can also form polyketides

OH

H2N

O
CH2

chlortetracycline

OH
OH O

OH

OH

malonamyl CoA
S CoA

O
NMe2

HO CH Cl
3

aureomycin

.. since our main interest is alkaloids we will

not study this series of compounds further,
however, there are alkaloids that incorporate
acetogenin pieces into a part of their structure.

ERYTHROMYCIN A

EXTENDER

methylmalonylCoA

BUILT FROM
3-CARBON UNITS

SCoA

6x

unchanged
O

reduced

OH

COOH

SCoA

CoA

STARTER

reduced

propionylCoA

reduced
dehydrated
reduced

OH

OH

OH

Enz

reduced

reduced

lactonization
O

oxidized

oxidized

D-desoamine

OH

HO
OH

NMe2

HO
O

oxidations

OH

OMe

erythromycin A

OH

L-cladinose

add sugars
O

OH
OH

QUINOLINE AND ACRIDINE ALKALOIDS

STARTER

1x
malonylCoA

OH
O

NH2

SCoA

SCoA
NH2

anthraniloyl-CoA
from anthranilic
acid, originating
from another
pathway
(shikimic acid)

QUINOLINE
TYPE
ALKALOIDS

3x
malonylCoA

OH

O
NH2

O
SCoA

N
H

OH

ACRIDINE
ALKALOIDS

NARINGENIN - A FLAVONOID
OH

OH

STARTER

3x malonyl-CoA

SCoA
O
O

SCoA
O

4-hydroxycinnamoyl-CoA

aldol

comes from the

shikimic acid pathway
OH
O

HO

A FLAVONOID
OH

naringenin

OH

H
O

HO

Michael
addition

found in grapefruit
flowers, fruit and rind
as the 7-rhamnogylcoside

OH