5. Polyketides
RA Macahig
FM Dayrit
Introduction
• Polyketides (which literally means “many ketone groups”)
make up a diverse biogenetic group which starts from acetylCoA to form a linear chain without extensive reduction. The
polyketide chain can cyclize to form aromatic rings or undergo
extensive derivatization.
• Polyketides rank among the largest group of secondary
metabolites in terms of diversity of structure and biological
diversity.
• Polyketide biosynthesis shares some similarities with the
initial steps of fatty acid acetyl polymerization. Like the fats,
the polyketide pathway probably arose early in biological
evolution before the rise of plants.
5. Polyketides (Dayrit)
2
Examples of polyketide natural products which illustrate
the wide variety of structures which comprise this group.
OH
CH3
O
OCH3
CO2H
HO
OCH3
HO
OH
O
O
OH
orsellinic acid
O
H3C
CH3O
Cl
O
griseofulvin
from Penicillium griseofulvum
alternariol
from the mould Alternaria tenius
O
O
H3C
CH3
HO
O
O
O
OH
H3C
CH3
O
O
OCH3
aflatoxin B1
from Apergillus species
macrolide antibiotic
erythromycin-type
from Streptomyces species
OR
CH3
O
OR
CH3
5. Polyketides (Dayrit)
3
Introduction
• The polyketides have great diversity of structures and
chemical functionalities. These structures range from
saturated macrocyclic lactones (macrolides), which are
unique polyketide metabolites, to various types of aromatic
compounds.
• Polyketides occur widely in bacteria, fungi and lichens, but
are of relatively minor occurrence in higher plants.
Bacteria, in particular Actinomycetes and Cyanobacteria,
are prolific sources of polyketides, many of which possess
antibiotic activity. Other significant polyketide producers
are Aspergillus (aflatoxins) and Penicillium and
Streptomyces species (tetracycline antibiotics).
5. Polyketides (Dayrit)
4
Overview of polyketide biosynthesis
Polyketides are produced from poly-acetyl intermediates
(poly-1,3-diketo compounds) which do not undergo complete
reduction, as in the case of the fats. The polyketides then
branch into two major pathways:
1. Aromatic compounds. The reactive 1,3-diketo groups
undergo intramolecular Claisen or lactonization reactions
forming cyclic compounds. Dehydration produces
aromatic compounds.
2. Macrolides. The keto- groups are reduced to alcohols,
which are subsequently dehydrated to form linear
compounds. The final products are macrocyclic esters.
Macrolides generally >12 carbon atoms in the ring.
5. Polyketides (Dayrit)
5
Aromatic
polyketides. Major
cyclization pathways
for a tetraketide
followed by
aromatization. O
c
c
d
d
O
O
O
O
7
8 C 6 5C 4 3C 2
C1
H3C
CH2
CH2
CH2
S-CoA
a
b a
b
a
b
d
c
O
S-CoA
O
O
O
S-CoA
O
O
O
O
S-CoA
O
O
O
O
Claisen
6
1
O
Aldol
2
7
(8)
CH3
O
C O
(8)
HO
S-CoA
O O
(1)
OH
CH3
(1)
HO
(1)
O
CO2H
O
OH
xanthoxylin
(a phloroglucinol)
HO
OH
orsellinic acid
(a resorcinol)
5. Polyketides (Dayrit)
O
CH2
(a -pyrone)
CH2
C
(8)
H3C
O
(8) CH3
(an -pyrone)
6
(1)
CO2H
Biosynthetic studies on polyketides (Arthur Birch)
4x
ratio:
H3C
O*
O*
O*
O*
O*
_
C
# O*
#
#
#
# S-CoA
#
1
------ = ----
14 C
#
1
--------- = ---18 O
*
HO
*
*
2
CH3
O
#
#
#
#
*
OH
1
*
OH
*OH O*
-H 2O*
#
#
*O
#
S-CoA
#
O*
orsellinic acid
The elucidation of the
polyketide pathway was
pioneered by Arthur
Birch in 1953. Birch
used 14C and 18O-labeled
acetate which he fed to
microorganisms to
establish the
incorporation pattern
and from this to
postulate the steps in the
biosynthesis of
polyketides.
#
4
------ = ---*
3
5. Polyketides (Dayrit)
7
Overview of polyketide biosynthesis
Birch proposal for polyketide biosynthesis:
1. Starting with a starter unit, C2 units are added to form the
polyketide chain (chain assembly).
2. Reduction and/or alkylation of the polyketide chain before
cyclization.
3. Intra- or intermolecular cyclization. (The more common
pathway is intramolecular cyclization.)
4. Secondary processes which modify the intermediate
product after cyclization, such as: halogenation, Omethylation, C-methylation, reduction, oxidation,
decarboxylation and skeletal rearrangement.
5. Polyketides (Dayrit)
8
CH3
O
Short-hand
representation of
polyketides:
o
O
a tetraketide
S-CoA
O
o
=
o
o
O
Variations in number of C2 units and mode of cyclization
Starting polyketide

Secondary metabolite
HO
triketide:
o
o
o
O
O
CH3
tetraketides:
(1)
CO2H
o
o
o
orsellinic acid
o
HO
OH
OH
o
O
o
CH3
o
xanthoxylin
(1)
o
HO
OH
5. Polyketides (Dayrit)
9
Variations in number of C2 units and mode of cyclization

Starting polyketide
Secondary metabolite
pentaketides:
HO
o
o
CH3
o
O
(1)
o
o
OH
O
OH
o
O
o
curvulinic acid
(Curvularia siddiqui)
CH3
o
o
o
CO2H
HO
(1)
OH
o
o
o
O
o
o
HO
(1)
O
CH3
hexaketide:
o
o
o
o
CH3O
CH3
O
o
diaporthin
(Endothia parasitica)
OH
o
OH
O
5. Polyketides (Dayrit)
10
Variations in number of C2 units and mode of cyclization
Starting polyketide

Secondary metabolite
heptaketide:
O
o
o
o
o
o
CH3O
O
o
o
monocerin
(Helminthosporium
monoceras)
CH3O
OH
OCH3
o
o
o
o
O
O
o
OCH3
O
o
o
O
H3C
CH3O
griseofulvin
(Penicillium
griseofulvum)
Cl
HO
CH3
o
o
o
o
OH
alternariol
(Alternaria tenius)
o
o
o
HO
O
O
5. Polyketides (Dayrit)
11
Variations in number of C2 units and mode of cyclization

Starting polyketide
Secondary metabolite
octaketide:
O
HO
o
o
o
o
o
CH3
o
o
CO2H
o
OH
O
O
o
o
o
curvularin
(Curvularia spp.))
o
o
o
HO
nonaketide:
HO
o
o
o
O
O
CH3
o
o
o
o
o
HO
O
Cl
o
o
o
o
o
o
o
O
radiciciol
(Nectaria radiciola)
O
o
O
HO
o
o
endocrocin
(Centralia endocrocea)
o
O
CH3O
CH3
OH
o
5. Polyketides (Dayrit)
HO
O
OH
nalgiovensin
(Penicillium
nalgiovensis)
12
O
A. Example of intermolecular cyclization.
Inter- vs.
intramolecular
cyclization:
A. Colletodiol;
B. Use of
labeling
experiments to
distinguish
intra- from
intermolecular
cyclization.
o
o
o
o
o
o
O
O
O
o
OH
OH
colletodiol
B. Use of labeling experiment to distinguish inter- vs. intramolecular cyclization.
[Me*]
o
o
o
o
o
o
o
o
o
o
-CO2
o
o
*
o
o
5. Polyketides (Dayrit)
-2CO 2
OH
OH
O
o
13
Biosynthesis of
macrolides:
Step-wise
chemical
transformations
and enzymes.
(from: The World of Polyketides, http://linux1.nii.res.in/)
5. Polyketides (Dayrit)
14
*
O
O
O
HS
HS HS HS
HS
S-CoA
H3C
HS HS HS
HS
S
_
O 2C
4 x
S -Co A
multi-enzyme complex
Hypothetical
scheme of the
biosynthesis of
phenol
polyketides
on the
Polyketide
Synthase
(PKS)
multienzyme
complex.
_
_
O 2C
_
O 2C
O 2C
o
_
*
_
O 2C
O 2C
o
O
O
O
O
O
S
S
_
O 2C
S
S
S
S
HS
S
S
*
S
O
O
_
O
O
_
base
O
O
*
O
O
S
HS
HS
HS
O
HS
CO2H
S
*
HO
O
O
OH
O
O
OH
5. Polyketides (Dayrit)
*
O
O
O
O
_
O 2C
O
*
15
S
Polyketide synthase (PKS)
The PKS family share a number of characteristics with the
family of fatty acid synthases (FAS): the PKS is a
multienzyme complex which is arranged so that the stepwise
transformations are carried out sequentially.
CO2H
H3C
OH
6-Methy lsalicy lic acid
O
OH
O
O
(from: The World of Polyketides, http://linux1.nii.res.in/)
O
CH3
CH3
H3C
Lov astatin
• ACP: acyl carrying protein
• KS: b-keto acyl synthase
• MAT: malonyl (acyl) transferase
• DH: dehydratase
• ER: enoyl reductase
• KR: keto reductase
• TE: thiol esterase
Hypothetical model for one type of PKS multienzyme system
which produces 6-methylsalicylic acid and lovastatin. The growing
chain is assembled on two multienzyme complexes.
5. Polyketides (Dayrit)
16
The biosynthetic pathway for the
fungal polyketide 6-methylsalicylic
acid (6-MSA). 6-MSA is assembled
KS: ketosynthase
MAT: malonyl-acetyl transferase
DH: dehydratase
KR: ketoreductase
ACP: acyl carrier protein
from four ketide units (one acetate and
three malonates). 6-MSAS contains the
following domains (in order): KS, MAT,
DH, KR and ACP. These act repeatedly
to catalyse three rounds of chain
extension, carrying out different levels
of reductive processing at each stage.
The first condensation is followed by
reaction with a second equivalent of
malonate extender unit, while the second
condensation is followed by reduction
and dehydration of the newly-formed
keto group. After the third cycle, the
chain undergoes cyclisation, dehydration
and enolisation. The absence of a
thioesterase domain suggests that release
of the chain from the PKS does not
occur by hydrolysis but by an alternative
mechanism which is still not verified.
(Staunton and Weismann, Nat. Prod. Rep., 2001, 18,
380–416)
Biosynthesis of macrolides on a modular Polyketide Synthase
(PKS) multienzyme complex.
(from: The World of Polyketides, http://linux1.nii.res.in/)
5. Polyketides (Dayrit)
18
Domain organization of the
erythromycin polyketide synthase.
Putative domains are represented
as circles. Each module
incorporates the essential KS, AT
and ACP domains, while all but
one include optional reductive
activities (KR, DH, ER).
The one-to-one correspondence
between domains and biosynthetic
transformations explains how
programming is achieved in this
modular PKS. (Staunton and
Weismann, Nat. Prod. Rep., 2001, 18, 380–
416)
5. Polyketides (Dayrit)
19
KS: ketosynthase
AT: acyltransferase
DH: dehydratase
ER: enoyl reductase
KR: ketoreductase
ACP: acyl carrier protein
TE: thioesterase
Predicted domain organization of the 6-deoxyerythronolide B synthase (DEBS) proteins.
KR indicates the inactive ketoreductase domain. The ruler shows the residue number
within the primary structure of the constituent proteins. The linker regions are also given in
proportion. (Staunton and Weismann, Nat. Prod. Rep., 2001, 18, 380–416)
5. Polyketides (Dayrit)
20
KS: ketosynthase
AT: acyltransferase
DH: dehydratase
ER: enoyl reductase
KR: ketoreductase
ACP: acyl carrier protein
TE: thioesterase
Inactivation of KR5 of DEBS results in the production of erythromycin analogues with
keto groups at the C-5 position. (Staunton and Weismann, Nat. Prod. Rep., 2001, 18, 380–416)
5. Polyketides (Dayrit)
21
KS: ketosynthase
ER: enoyl reductase
TE: thioesterase
AT: acyltransferase
KR: ketoreductase
DH: dehydratase
ACP: acyl carrier protein
Inactivation of ER4 results in an analogue of erythromycin with a double bond at the
expected site. (Staunton and Weismann, Nat. Prod. Rep., 2001, 18, 380–416)
5. Polyketides (Dayrit)
22
Domain organization of the rapamycin polyketide synthase
(RAPS). As with the erythromycin PKS there is a co-linearity
between the sequence of modules and the order of biosynthetic
steps. (Staunton and Weismann, Nat. Prod. Rep., 2001, 18, 380–416)
5. Polyketides (Dayrit)
23
What is the link between FAS and PKS?
The PKS system is likely derived from bacterial FAS. Different
PKS pathways in bacteria illustrate the selective evolutionary
advantage that multiple secondary metabolite biosyntheses
confer to individual bacteria and taxonomic kingdoms.
KS: ketoacyl synthase
AT: acyl transferase
DH: dehydratase
ER: enoyl reductase
ACP: acyl carrying protein
Organization of fatty acid synthases (FAS) and polyketide
synthases (PKS). (Jenke-Kodama et al. J Mol Bio Evol 2005)
5. Polyketides (Dayrit)
24
What is the link between FAS and PKS?
Common sequence of reactions performed by FAS and PKS.
Enzymes in a PKS module.
(Jenke-Kodama et al. J Mol Bio
Evol 2005)
KS: ketoacyl synthase
ACP: acyl carrying protein
KR: ketoreductase
DH: dehydratase
ER: enoyl reductase
5. Polyketides (Dayrit)
25
Common enzymes in aromatic polyketides
O
O
-
O2C
S-CoA
min PKS
starter unit
R
O
O
O
O
O
O
KS-CLF
O
O
O
O
SACP
R
15
O
9
O
O
O
SACP
OH
C-9 KR
OH
O
OH
R
O
O
CYC
O
S-ACP
R
O
O
5
O
O
O
ARO
O
SACP
HO
R
O
O
9
OH
O
O
O
SACP
principal common intermediate
with varying R group
common aromatic intermediate
Four proteins comprise the minimal PKS: ketosynthase (KS),
chain length factor (CLF), acyl carrier protein (ACP), and a
malonyl-CoA:ACP transacylase (MAT) which is usually recruited
from fatty acid synthases. Other common enzymes include:
aromatase (ARO) and cyclase (CYC). (Ridley et al., PNAS, 2008,
105:4595-4600)
5. Polyketides (Dayrit)
26
“Deciphering the mechanism for the assembly of aromatic
polyketides by a bacterial polyketide synthase,” Shen and Hutchinson, Proc. Natl.
Acad. Sci. USA, 93, 6600-6604, June 1996.
aberrant
cyclization
Acy l-CoA
+
9 Mal-CoA
unidentif ied products
O
O
TcmJKLM
O
O
O
O
O
O
HO
SCoA
O
OH
TcmN
O
CH3
O
OH
0
Tetracenomy cin PKS
7 kb
K
J
M
L
OH
OH
CO2H
CH3
Tcm F2
N
TcmI
O
O
CH3O
OH
HO
TcmN
O
OH
Tcm B3
CH3
OH
TcmH
CO2H
OH
HO
OH
CO2H
CO2H
OH
O
OH
CH3
Tcm D3
OH
O
OH
CH3
Tcm F1
The optimal Tcm PKS is a complex consisting of the TcmJKLMN proteins. It is
the integrity of this complex that maximizes the efficiency for the synthesis of
aromatic polyketides from acetyl- and malonyl-CoA.
5. Polyketides (Dayrit)
27
Polyketide modifications:
before cyclization and after cyclization (secondary processes). Note:
F: fungi; P: plant refers to the biological system where the process has been studied. The number of 
marks denote frequency of occurrence;  denotes not observed.
Modification
1. reduction
2. oxidation
3. C-methyation
4. O-methylation
5. C-prenylation
6. O-prenylation
7. C-glycosylation
8. O-glycosylation
9. decarboxylation
10. aromatic radical coupling
Before cyclization
 (F)

 (F)

 (F,P)





After cyclization
(Secondary process)
?
 (F,P)

 (F,P)
 (F,P)
 (P)
 (P)
 (P)


• The various Kingdoms exhibit different characteristics of their PKS
enzymes. In the microbial kingdom, at least three types of PKS
enzymes have been recognized.
5. Polyketides (Dayrit)
28
Reduction and alkylation of the polyketide chain before
cyclization. The polyketide can be reduced to the alcohol
and be subsequently dehydrated to produce the double bond.
The resulting aromatic ring will not have a OH substituent in
the particular position.
O
O
O
+
S-CoA
_
2 x O2C
O
O
S-CoA
S-CoA
1. NADPH
2. -H2O
O
O
O
_
O2C
O
S-CoA
S-CoA
S-CoA
O
O
CH3
o
o
CO2H
6-methylsalicylic acid
from Penicillium urticae
o
OH
5. Polyketides (Dayrit)
29
Reduction and alkylation of the polyketide chain before
cyclization. The polyketide can be C-alkylated (e.g., with
methyl or isopentyl groups) prior to cyclization although it
may be difficult to determine whether C-alkylation is carried
out before or after cyclization.
OH
O
CH3
OH
[CH3 ]
o
o
o
O
HO
H3C
CH3
OH
o
HO
[CH3 ]
H3C
CH3
clavatol
5. Polyketides (Dayrit)
O
CH3
HO
30
Secondary processes: examples of oxidation, decarboxylation and methylation.
A. Gentisic acid
CH3
CO2H
CO2H
CHO
CHO
HO
CO2H
[O]
[O]
-CO2
OH
OH
OH
OH
gentisic acid
6-methylsalicylic acid
B. Fumigatin
CH3
CH3
CO2H
1. [O]
2. [CH3]
-CO2
HO
OH
HO
CH3
CH3
OH
orsellinic acid
O
HO
[O]
HO
OH
OCH3
HO
O
OCH3
fumigatin
5. Polyketides (Dayrit)
31
Erythromycin, first
*
isolated from
Streptomyces
erythreus from soil
samples from Iloilo
sent by Abelardo
Aguilar in 1949. It
was first marketed
by Eli Lilly as
Ilosone®.
R.B.Woodward
accomplished its
stereospecific
synthesis in 1981.
It is used for the
treatment of grampositive bacterial
infections.
O
O
+ 6
S-CoA
S-CoA
starter unit
7
o
9
o
11
o
o5
CO2H
13
o
Erythromycin
A
B
C
R1
OH
H
OH
R2
1
1
1
o
o
1
R3
2
2
3
3
*
CH3
O
O
9
1 : D-desosamine:
N(CH3)2
OH
HO
2 : L-cladinosine:
O
CH3
CH3
11
HO
*
7
OR1
OR2
O
1
3
O
OR3
CH3
HO
3 : L-mycarose:
O
CH3
OH
5. Polyketides
(Dayrit)
CH
3
OH
5
13
32
5. Polyketides (Dayrit)
33
Intramolecular aromatic radical coupling: biosynthesis of griseofulvin (from a fungus, Penicillium
griseofulvum) involves extensive secondary modification of a heptaketide.
OH
o
o
O OH
o
OH
o
o
o
o
HO
OH
+ 2 [CH3 ]
CH3
OH
O OCH
3
OH
OH
CH3 O
CH3 O
CH3
O OCH
3
OH
griseophenone C
OH
O OCH
3
[O]
OH
Cl
O
.
CH3 O
CH3
Cl
O
O.
CH3 O
O
CH3
O OCH
3
.
.
OH
CH3 O
OH
CH3
griseophenone B
+ [CH3 ]
OCH3
OH
OH
Cl
O OCH
3
+ [Cl],
-[H]
CH3
Cl
griseophenone A
OH
O
OH
O
OCH3
OCH3
O
CH3 O
O
CH3
Cl
5. Polyketides
(Dayrit)
griseofulvin
+ 2 [H]
O
CH3 O
O
CH3
Cl
dehydrogriseofulvin
34
Nature of starting unit
Fatty acid s ynthas e (FAS)
Polyk e tide s ynthas e (PKS)
O
O
O
O
C
C
H3C
H3C
SCoA
Acety l CoA
SCoA
Acety l CoA
SCoA
OH
Propiony l CoA
Benzoy l CoA
O
O
C
HO
O
O
C
CH2
SCoA
Malony l CoA
O
OH
Buty ry l CoA
SCoA
R2
O
O
C
CH
R1
Isobuty ry l CoA
O
C
HO
O
OH
SCoA
CH3
Methy lmalony l CoA
R
OH
Hexanoy l CoA, R=C
5H11
Octanoy l CoA, R=C
7H15
O
H3C
SCoA
Acetoacety l CoA
O
R1 R2
Cinnamoy l CoA
H
p-Coumaroy l CoA H
Caf f eoy l CoA
OH
Feruloy l CoA
OH
H
OH
OH
OMe
O
O
MeHN
H2N
SCoA
SCoA
Acetamidoacety l CoA
N-Methy lanthrany loy l CoA
5. Polyketides (Dayrit)
35
Nature of starting unit
Examples of metabolites where the starting unit is not acetyl-CoA. In the case of tetracycline, extensive
secondary processes take place.
o
CO2H
OH
O
OH
o
o
o
o
o
O
HO
o
o
o
o
HO
OH
7S, 9R, 10R--pyrramycinine
Cl H C
3
o
o
o
o
o
H
N(CH3)2
o
o
o
OH
o
OH
CONH2
CONH2
OH
OH
O
OH
O
tetracycline
5. Polyketides (Dayrit)
36
Metabolites from polyketides
The polyketide metabolites can be classified into five groups:
1. Phenols
2. Quinones
Aromatic compounds
3. Aflatoxins
4. Tetracyclines
5. Macrolide antibiotics
1. Phenols
Cyclization and aromatization of polyketides form phenols as
the initial product. In plants however, phenols are also
formed from the shikimate pathway. Therefore, phenols and
their methylated derivatives are common natural products.
Some common phenols are formed via different pathways.
5. Polyketides (Dayrit)
37
Metabolites from polyketides
2. Quinones
Quinones often occur as the final product from a series of
oxidation reactions on mono- or polycyclic aromatic ring
systems.
The biosynthetic pathway differs in microorganisms and
plants. In microorganisms, quinones arise predominatly via
the polyketide pathway. In plants, however, quinones can
arise via the polyketide or shikimate pathways and
sometimes via the mixed biosynthetic route involving the
ring-formation of an added terpenoid unit. The presence of
multiple pathways to the quinone ring system may reflect the
importance of this type of functionality.
5. Polyketides (Dayrit)
38
In microorganisms:
[O]
polyketide
Overview of biosynthesis
of quinones. Depending
on the organism,
quinones can arise via
the polyketide or
shikimate pathways.
• Aromatic metabolites in
microorganisms are likely
to be formed via the
polyketide pathway while
aromatic compounds in
plants are likely to come
from the shikimate
pathway.
aromatic compound
quinone
In plants:
[O]
polyketide
aromatic compound
quinone
quinone
shikimate
aromatic compound
+ terpene
[O]
quinone
(mixed metabolite)
quinone from shikimate:
OH
quinones from shikimate + terpene:
OH
O
OH
O
H
OH
CO2H
OH
homogentisic acid
alkarinin
O
R
H
O
39
n
ubiquinones: R = H, CH3 ; n = 4-13
Metabolites from polyketides
1,4-Benzoquinone
1,4-Benzoquinone itself is the simplest member of this
group. However, because it is toxic, it is not found in this
form but rather as a protected precursor, such as arbutin, a
glycosylated 1,4-hydroquinone, the reduced form of 1,4benzoquinone.
O-Glu
Arbutin occurs in the leaves of various
plant species and may be a plant
defense compound. The ability to
detoxify phenols or to store them as
glycosides appears to be a common
characteristic of plants.
5. Polyketides (Dayrit)
OH
Arbutin
40
5. Polyketides (Dayrit)
41
A. Plants store precursors of para-quinone in various glycosylated forms.
O-Glucose
Para-quinone is a toxic
compound which
various organisms use.
A. Various trees secrete
a precursor (arbutin) to
“clear” its surroundings
of competing plants;
B. The bombardier
beetle produces paraquinone in its collecting
bladder from parahydroquinone + H2O2.
OH
arbutin
O-Glu-O-Glu
O-Glu-O-Glu-O-Glu
OH
OH
O
para-quinone
(toxic)
O
B. Para-quinone as a defensive secretion of the bombardier beetle.
collecting bladder
OH
lobe
+ H2 O2
explosion
chamber with
enzyme gland
OH
O
+ H2 O + heat
5. Polyketides (Dayrit)
O
42
5. Polyketides (Dayrit)
43
Metabolites from polyketides
Aflatoxins
• The aflatoxins are a group of fungal metabolites which have
closely similar chemical structures, the most evident feature
being two fused furan rings.
• Aflatoxins were first discovered following investigations into
the deaths of turkeys after being being fed mouldy peanuts.
O
O
O
O
O
OCH3
af latoxin B1
f rom Apergillus species
5. Polyketides (Dayrit)
44
Metabolites from polyketides
Aflatoxins
• Aflatoxins are among the most toxic naturally-occuring
compounds known. They are potent hepatocarcinogens and
cause lesions in the mammalian liver. They are toxic to rats
down to a dose level of 1 g/day.
• Various strains of Aspergillus produce aflatoxins, in
particular, A. parasiticus, A. versicolor and A. flavus.
Aspergillus fungi are usually encountered growing on various
types of organic matter, especially in damp places. They cause
the decay of many stored fruits and vegetables, bread, leather
goods and various fabrics.
• Aflatoxins are one of the major causes of concern in our
copra industry. The European Commission limit is currently set
at 5 ppb.
5. Polyketides (Dayrit)
45
O
[O]
HO
o
o
o
o
o
o
o
o
o
decaketide
Aflatoxins
make up a
family of
polyketide
metabolites.
The very
complex
biosynthesis
of aflatoxins
was
elucidated
by George
Büchi.
OH
o
OH
O
OH
O
O
+2[H]
O
+2[H], -H 2O, +2[H]
O
O
HO
O
HO
+
H
O
OH
HO
OH
O
OH
OH
OH
O
OH
OH
-H2 O
O
O
HO
[O]
O
HO
OH
O
OH
OH
O
OH
O
OH
OH
-H 2O
O
HO
OH
CHO CHO
O
-C2
O
HO
OH
OH
OH
O
HO
O
O
OH
O-H
CHO
O
O
OH
OH
O-H
O
OH
O
[O]
averufin
O
O
HO
OH
OH
O
O
OH
versicolorin B
versicolorin A
5. Polyketides (Dayrit)
[O], Bayer-Villiger
46
O
+2[H]
O
HO
OH
O
HO
[O]
Bayer-Villiger
O
O
CO2H HO
OH
OH
O
O
OH
versicolorin A
+2[H],
-CO2
O
H
[O]
O
H
O
OH
OH
[O]
H
O
H
[O]
H
O
O
OH
OH
sterigmatocystin
O
O
OH
O
O
HO
O
O
O
OH
OH
H
O
O
O
H
O
HO2C
O
O
OH
O
H
O
O
O
OH
H
H
H
O
O
H
O
O
-CO 2 ,
+[CH 3 ],
-H 2 O
O
O
H
O
O
O
H
O
O
O
O
O
O
OH
OCH3
aflatoxin B1
OH
5. Polyketides (Dayrit)
CO2H
[CH 3 ]
_ O
CO2H
OH
47
O
[O]
HO
o
o
o
o
o
OH
o
o
o
o
o
decaketide
OH
O
OH
O
O
+2[H]
O
+2[H], -H 2O, +2[H]
O
O
HO
O
HO
+
H
O
OH
HO
OH
O
OH
OH
OH
O
OH
OH
-H2 O
O
O
HO
[O]
O
HO
OH
O
OH
OH
O
OH
O
OH
OH
OH
O-H
[O]
averufin
-H 2O
O
O
HO
O
5.
OH
-C2
Polyketides
(Dayrit)
CHO CHO
HO
O
OH
48
O-H
OH
O
OH
OH
OH
O
OH
OH
-H2 O
O
O
HO
[O]
O
HO
OH
O
OH
OH
O
OH
O
OH
OH
O-H
-H 2O
O
O
HO
OH
CHO CHO
O
-C2
O
HO
OH
OH
OH
O
HO
O
O
OH
O-H
CHO
O
O
OH
OH
[O]
averufin
OH
O
OH
OH
O
O
OH
versicolorin B
versicolorin A
5. Polyketides
[O], Bayer-Villiger
O
HO
O
(Dayrit)
49
O
+2[H]
O
HO
OH
O
HO
[O]
Bayer-Villiger
O
O
CO2H HO
OH
OH
O
O
OH
versicolorin A
+2[H],
-CO2
O
H
[O]
O
H
O
OH
OH
[O]
H
O
O
H
O
OH
O
O
OH
O
O
HO
O
O
OH
OH
sterigmatocystin
H
[O]
O
H
O
O
5. PolyketidesOH
(Dayrit)
O
OH
H
O
HO2C
O
O
O
H
O
O
O
50
OH
O
H
[O]
O
H
O
OH
OH
[O]
H
O
OH
OH
H
[O]
H
O
O
sterigmatocystin
O
O
OH
O
O
HO
O
O
O
OH
OH
H
O
O
O
H
O
HO2C
O
O
OH
O
H
O
O
O
OH
H
H
H
O
O
H
O
O
-CO 2 ,
+[CH 3 ],
-H 2 O
O
O
H
O
H
O
O
O
O
O
O
OH
OCH3
aflatoxin B1
5. Polyketides (Dayrit)
CO2H
O
O
OH
[CH 3 ]
_ O
CO2H
OH
51
+2[H]
[O]
[CH 3]
CH3
OH
OH
o
o
o
o
o
NH2
o
o
o
o
CONH2
HO
CH3 H
HO
OH
OH
[O]
CH3
O
H
O
O
OH
OH
NH2
NH2
Biosynthesis of
tetracyclines from
Streptomyces
species.
HO
+H 2O
CH3
HO
O
O
HO
O
CH3
O
HO
OH
O
OH
NH2
NH2
OH
OH
HO
O
O
H
H
OH
HO
O
O
HO
O
CH3
H
HO
O
O
O
+2[H]
CH3
N(CH3)2
OH
H
+[NH2 ],
+2[CH3 ]
OH
OH
NH2
NH2
OH
OH
HO
Cl
CH3
H
HO
O
O
HO
O
HO
O
O
O
[Cl]
N(CH3)2
OH
H3C
OH
R
H
NH2
OH
HO
HO
O
O
O
N(CH3)2
OH
A
B
C
OH
O
OH
D
CONH2
OH
Cl H C
3
OH
H
O
R=H : tetracycline
R=OH : terramycin
N(CH3)2
OH
A
B
C
OH
O
OH
D
OH
aureomycin
CONH
5. Polyketides
(Dayrit)
2
O
52
+2[H]
[O]
[CH 3]
CH3
OH
OH
o
o
o
o
o
NH2
o
o
o
o
CONH2
HO
CH3 H
Biosynthesis of
tetracyclines
from
Streptomyces
species.
HO
OH
O
[O]
CH3
O
H
OH
O
OH
OH
NH2
NH2
HO
+H 2O
CH3
HO
O
O
HO
O
CH3
O
HO
OH
O
H
OH
NH2
NH2
OH
OH
HO
O
O
H
OH
HO
O
O
HO
O
CH3
H
HO
O
O
O
+2[H]
CH3
N(CH3)2
OH
H
+[NH2 ],
+2[CH3 ]
OH
OH
NH2
NH2
OH
OH
HO
Cl
CH3
HO
O
O
O
[Cl]
5. Polyketides
(Dayrit)
H
N(CH3)2
OH
HO
HO
O
O
53
O
HO
+H 2O
CH3
HO
O
O
HO
O
CH3
O
HO
OH
O
H
OH
NH2
NH2
OH
OH
HO
O
O
H
OH
HO
O
O
HO
O
CH3
H
HO
O
O
O
+2[H]
CH3
N(CH3)2
OH
H
+[NH2 ],
+2[CH3 ]
OH
OH
NH2
NH2
OH
OH
HO
Cl
CH3
H
HO
O
O
HO
O
HO
O
O
O
[Cl]
N(CH3)2
OH
H3C
OH
R
H
NH2
OH
HO
HO
O
O
OH
A
O
N(CH3)2
B
C
D
CONH2
OH
OH
Cl H C
3
OH
H
O
OH
O
R=H : tetracycline
R=OH : terramycin
N(CH3)2
OH
A
B
C
aureomycin
D
CONH
2
5. Polyketides
(Dayrit)
OH
OH
O
OH
O
54
Summary
FAS and PKS probably share an evolutionary history. Like
the fats, polyketides also arise from polymerization of
acetyl CoA. The key features and steps are:
1. Alternative starter units are used, in particular in the
formation of tetracyclic antibiotics and macrocylic
lactones.
2. No reduction of the carbonyls, or reduction to alcohol
level only.
3. Cyclization via Claisen displacement or aldol reaction.
There are many modes of cyclization depending on the
chain length.
5. Polyketides (Dayrit)
55
Summary
4. Aromatization often follows with loss of H2O.
5. wider range of compounds are produced: macrocyclic
lactones, phenols, quinones, and polycylic aromatic
compounds.
6. Polyketides are attractive research targets because of
their strong and varied biological activity, the modular
nature of the genetic system and polyketide synthases,
and relatively accessible biosynthetic expression
systems.
5. Polyketides (Dayrit)
56