POLYKETIDES,

1
POLYKETIDES, ACETOGENINS
2
ACETYL COENZYME A
A TWO-CARBON BUILDING BLOCK
Acetyl CoA
Can be used like a molecular Lego piece ..
well , sort of ..
3
CLAISEN CONDENSATION
LIKE THE ALDOL CONDENSATION BUT
WITH ESTERS
REVIEW
REMEMBER CHEM 353
a b-ketoester
CH3CH2OH
Acidic a-hydrogens are removed in strong base to
make an enolate anion which adds to the CO of
another molecule.
-
..
..



..
-
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CONCATENATION OF ACETATE UNITS
acetic acid
acetyl CoA
acetate unit
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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.
WHY THIOESTERS ?
Differences between an oxygen ester and a
thioester
Thioesters are more prone to enolization.
Thioesters are more reactive.
B
ATP
ADP
Biotin
malonyl CoA
Biotin-COOH
6
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
..
x2
- CO2
x1
acetyl CoA
x3
STARTER
x5 x4
a polyketide chain
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THERE ARE TWO CARBONYL GROUPS IN THE 2-UNIT
POLYKETIDE CHAIN
EITHER ONE CAN REACT
..
1
2
- CO2
LINEAR
BRANCHED
mevalonic acid
POLYKETIDE CHAINS
TERPENES
ACETOGENINS
STEROIDS
8
THE ASSEMBLY ENZYMES
acetyl - malonyl transferases
acetylCoA
starter
H
..
cys -S
cys -SH
B
..
- CO2
-SH
-S
B
malonylCoA
..
extender
- CO2
-SH
etc.
-S
B
..
more malonylCoAs
-SH
- CO2
..
-S
-SH
acyl carrier protein (ACP)
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BUILDING THE CHAIN ON A FLEXIBLE LINK
ANOTHER MODEL OF THE ENZYME
- CO2
transfer
Malonyl-CoA
Growing chain
- CO2
etc
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POLYKETIDES ACCETOGENINS
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WE WILL LOOK AT POLYKETIDES FIRST
1 2 3 4
Polyketides are the precursors of the class of
natural products called acetogenins
internal aldol condensation
H2O
hydrolysis
- CoASH
enolization
- H2O
Orsellinic acid
dehydration
( Lichen spp )
makes aromatic ring
an acetogenin
made from acetate units
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SOME OTHER SIMPLE ACETOGENINS
1) enolization 2) SAM
internal Claisen
Eugenone
( oil of cloves )
(found in Lichen )
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ANTHRAQUINONE LAXATIVES
emodin
physicon
Penicillium spp Rhamnus spp Rumex spp
Senna Casacra Rhubarb Aloes Frangula
rhein
aloe-emodin
cascaroside
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GRISEOFULVIN
Penicillium griseofulvin
Anti-fungal, antibiotic for toenail and skin
infections absorbed from stomach, concentrated in
skin.
SAM
..
Aldol
Cl
Claisen
reson.
O
.
.
.
.
SAM
FADH2
griseofulvin
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MACROLIDES (LARGE RINGS)
aldol
9 units
aromatize
NADPH
lactonize
..
NADPH, then dehydrate
NADPH, then dehydrate, then FADH2
macrolide antibiotic
acetylCoA 8 malonylCoA
The various reductions may be performed during
the chain extension steps rather than afterward.
zearalenone
Gibberalla zeae
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DIFFERENT STARTERS AND EXTENDERS
THE METHOD IS NOT RESTRICTED TO ACETATE
UNITS ONLY
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MALONAMYL CoA STARTER
malonamylCoA
starter
H
..
cys -S
cys -SH
B
..
- CO2
-SH
-S
B
malonylCoA
..
extender
- CO2
-SH
etc.
-S
B
..
more malonylCoAs
-SH
- CO2
..
-S
-SH
acyl carrier protein (ACP)
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TETRACYCLINES
actually starts from malonamyl CoA which can also
form polyketides
chlortetracycline
malonamyl CoA
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.
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ERYTHROMYCIN A
unchanged
EXTENDER
reduced dehydrated reduced
methylmalonylCoA
BUILT FROM 3-CARBON UNITS
reduced
6x
reduced
reduced
reduced
propionylCoA
STARTER
lactonization
oxidized
oxidized
D-desoamine
oxidations
add sugars
L-cladinose
erythromycin A
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QUINOLINE AND ACRIDINE ALKALOIDS
1x malonylCoA
QUINOLINE TYPE ALKALOIDS
STARTER
3x malonylCoA
anthraniloyl-CoA
from anthranilic acid, originating from
another pathway
(shikimic acid)
ACRIDINE ALKALOIDS
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NARINGENIN - A FLAVONOID
STARTER
3x malonyl-CoA
4-hydroxycinnamoyl-CoA
aldol
comes from the shikimic acid pathway
A FLAVONOID
Michael addition
naringenin
found in grapefruit flowers, fruit and rind as
the 7-rhamnogylcoside