Po Like Tida

5.
Polyketides
RA Macahig
FM Dayrit
Introduction
Polyketides (which literally means many ketone groups)
make up a diverse biogenetic group which starts from acetyl-
CoA 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 OCH3
CH3 O
CO2H OCH3
HO
O
CH3O O
HO OH O OH H3C
orsellinic acid O Cl
alternariol griseofulvin
from the mould Alternaria tenius from Penicillium griseofulvum
O
O
H3C CH3
HO OH macrolide antibiotic
O O O H3C erythromycin-type
CH3 from Streptomyces species
O O OR
CH3
OCH3
O OR
aflatoxin B1 CH3
from Apergillus species
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).
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.
Aromatic d
c d c
polyketides. Major 7
O O O O
8 C 6 5C 4 3C 2 C1
cyclization pathways H3C CH2 CH2 CH2
a
S-CoA
b a b
for a tetraketide
followed by a
d
b c
aromatization. O
O
S-CoA
O O
O O S-CoA
O
O S-CoA
O
O O O S-CoA
O O O
Claisen
6 1 O
Aldol
(8)
2 7
CH3
C O O
(8)
HO (1) OH CH3
HO (1) O
(1)
CO2H
O (8)
H3C O CH2 (1)
CO2H
OH HO OH CH2 (a -pyrone)
orsellinic acid
xanthoxylin C O
(a resorcinol)
(a phloroglucinol)
5. Polyketides (Dayrit) (8) CH3 6
(an -pyrone)
Biosynthetic studies on polyketides (Arthur Birch)
O* O* O* O* O*
4x C _ The elucidation of the

H3C # O* # # # # S-CoA
polyketide pathway was
ratio:
14 C # 1 # 1 pioneered by Arthur
--------- = ---- ------ = ----
Birch in 1953. Birch
18 O * 2 * 1
used 14C and 18O-labeled
acetate which he fed to
microorganisms to
O
establish the
CH3 * *OH O* incorporation pattern
# # -H 2O*
OH # # S-CoA and from this to
# #
*
HO
*
OH # # postulate the steps in the
*O O*
biosynthesis of
orsellinic acid
polyketides.
# 4
------ = ----
* 3
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, O-
methylation, C-methylation, reduction, oxidation,
decarboxylation and skeletal rearrangement.
O CH3
Short-hand o o
a tetraketide O =
representation of S-CoA
o o
polyketides: O O
Variations in number of C2 units and mode of cyclization

Starting polyketide Secondary metabolite
HO
triketide:
o
o o
O O
tetraketides: CH3
(1)
CO2H
o o
orsellinic acid
o o HO OH
OH O
o o
CH3
xanthoxylin
o o (1)
HO OH
pentaketides:
HO CH3
o o o
(1) O
o o
OH O
OH O
o o
CH3 curvulinic acid
(Curvularia siddiqui)
o o o
CO2H
HO (1)
OH O
o o
o o o
HO (1) O CH3
hexaketide:
CH3O CH3
o o o o diaporthin
(Endothia parasitica)
O OH
o o
OH O
heptaketide:
O
o o o o o CH3O
monocerin
(Helminthosporium
o o O
CH3O monoceras)
OH O
OCH3 O
o o o
OCH3
O griseofulvin
o o o o
(Penicillium
CH3O O
griseofulvum)
H3C
Cl
HO CH3
o o
alternariol
o o (Alternaria tenius)
OH
o o
o HO O
O
octaketide: O
HO CH3
o o o o endocrocin
(Centralia endocrocea)
o o o o CO2H
OH O
O O
curvularin
o o o HO (Curvularia spp.))
o o o o o
HO O
nonaketide: HO O CH3
O
o o o o radiciciol
O (Nectaria radiciola)
o o o o o
HO
O
Cl
O
o o o o o
CH3O CH3
nalgiovensin
(Penicillium
o o o o
OH
nalgiovensis)
HO O OH
A. Example of intermolecular cyclization. O
o o o O O
Inter- vs. o o o o O
OH
intramolecular OH
cyclization: colletodiol
A. Colletodiol; B. Use of labeling experiment to distinguish inter- vs. intramolecular cyclization.

B. Use of
labeling [Me*]
experiments to o o o
distinguish -CO2
o o o o
intra- from *
intermolecular
cyclization.
o o o o
-2CO 2 OH OH O
o o o o
Biosynthesis of
macrolides:
Step-wise
chemical
transformations
and enzymes.
(from: The World of Polyketides, http://linux1.nii.res.in/)
O O *
O
_
HS HS HS HS HS H3C S-CoA HS HS HS HS S 4 x O 2C
S -Co A
multi-enzyme complex
Hypothetical
scheme of the *
_ _ _ _
O 2C
_ _ _ O 2C O 2C O 2C
biosynthesis of O 2C O 2C O 2C o
O *
O O O O
phenol O O O O
S S S S S
S S S S HS
polyketides
on the
o *
Polyketide O
S
O
Synthase O
O
_
_
(PKS) O base O *
multienzyme O O
O
S HS HS HS HS
complex.
CO2H S
O
HO *
O
OH
O
O
OH O
*
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 ACP: acyl carrying protein
H3C OH KS: b-keto acyl synthase
MAT: malonyl (acyl) transferase
6-Methylsalicylic acid DH: dehydratase
ER: enoyl reductase
O OH
KR: keto reductase
O
O
TE: thiol esterase
O
CH3 CH3
Hypothetical model for one type of PKS multienzyme system
H3C which produces 6-methylsalicylic acid and lovastatin. The growing
Lovastatin
chain is assembled on two multienzyme complexes.
The biosynthetic pathway for the
fungal polyketide 6-methylsalicylic
acid (6-MSA). 6-MSA is assembled
from four ketide units (one acetate and
three malonates). 6-MSAS contains the
KS: ketosynthase
following domains (in order): KS, MAT,
MAT: malonyl-acetyl transferase DH, KR and ACP. These act repeatedly
DH: dehydratase
KR: ketoreductase
to catalyse three rounds of chain
ACP: acyl carrier protein 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,
380416)
Biosynthesis of macrolides on a modular Polyketide Synthase
(PKS) multienzyme complex.
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)
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, 380416)
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, 380416)
KS: ketosynthase AT: acyltransferase DH: dehydratase
ER: enoyl reductase KR: ketoreductase ACP: acyl carrier protein
TE: thioesterase
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, 380416)
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, 380416)
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)
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
Common enzymes in aromatic polyketides
O O R O O R
O 15
-
O2C min PKS O KS-CLF O
S -C oA O O O O O O O
9
starter unit O S AC P O S AC P
OH
C-9 KR
R O O R
R OH O
OH O
O O
CYC ARO O O
O O O O O
9
O O
5 S AC P HO S AC P
S -AC P OH
common aromatic intermediate principal common intermediate

with varying R group
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)
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 unidentified products
O O
Acyl-CoA TcmJKLM
+ O O O HO OH
9 Mal-CoA O SCoA
TcmN
O O O O O
CH3 CO2H
OH OH OH CH3
0 7 kb
Tcm F2
Tetracenomycin PKS J K L M N
TcmI
O O
CH3O OH HO OH HO OH
TcmN TcmH
CO2H CO2H CO2H
OH O OH CH3 OH O OH CH3 OH O OH CH3
Tcm B3 Tcm D3 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.
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 Before cyclization After cyclization

(Secondary process)
1. reduction (F) ?
2. oxidation (F,P)
3. C-methyation (F)
4. O-methylation (F,P)
5. C-prenylation (F,P) (F,P)
6. O-prenylation (P)
7. C-glycosylation (P)
8. O-glycosylation (P)
9. decarboxylation
10. aromatic radical coupling
The various Kingdoms exhibit different characteristics of their PKS

enzymes. In the microbial kingdom, at least three types of PKS
enzymes have been recognized.
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 O O
_
+ 2 x O2C
S-CoA S-CoA S-CoA
1. NADPH
2. -H2 O
O
O O _ O
O2C
S-CoA
S-CoA S-CoA
O O
CH3
o o CO2H
6-methylsalicylic acid
from Penicillium urticae
o
OH
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 O
[CH3 ] HO
o o H3C
CH3
OH O
o o
HO H3C
CH3
CH3
[CH3 ]
clavatol HO
Secondary processes: examples of oxidation, decarboxylation and methylation.
A. Gentisic acid
CH3 CHO CHO CO2H
CO2H CO2H HO
[O] -CO2 [O]
OH OH OH OH
6-methylsalicylic acid gentisic acid
B. Fumigatin
CH3 CH3 CH3 CH3
CO2H 1. [O] HO O
-CO2 2. [CH3] [O]
HO OH HO OH HO OH HO O
orsellinic acid OCH3
OCH3
fumigatin
O O 9 7
Erythromycin, first o o
*
isolated from S-CoA + 6 S-CoA 11 o o5
Streptomyces starter unit CO2H
13o
erythreus from soil o
o
3
1
samples from Iloilo Erythromycin R1 R2 R3
A OH 1 2 *
sent by Abelardo B H 1 2
Aguilar in 1949. It C OH 1 3
was first marketed

CH3
by Eli Lilly as O
O
Ilosone. 1 : D-desosamine: 9
N(CH3)2
R.B.Woodward 7
11
accomplished its OH
HO OR1
OH
13 5
stereospecific HO O
*
O OR2
2 : L-cladinosine:
synthesis in 1981. CH3 1 3
CH3
O OR3
It is used for the
treatment of gram- CH3
positive bacterial HO O
3 : L-mycarose: CH3
infections. OH
5. Polyketides
CH
(Dayrit) 32
3
Intramolecular aromatic radical coupling: biosynthesis of griseofulvin (from a fungus, Penicillium
griseofulvum) involves extensive secondary modification of a heptaketide.
OH O OH
o o o
OH
o o o o
HO OH
+2 [CH3 ]
CH3
OH O OCH OH O OCH
3
3
+[Cl],
-[H]
OH OH
CH3 O OH CH3 O OH
CH3 CH3
Cl
+[CH3 ] griseophenone B griseophenone C
OCH3 O OCH OH O OCH OH O OCH

3
3 3
[O]
OH O . . O
CH3 O OH . CH3 O O .
CH3 O O
CH3 CH3 Cl CH3
Cl Cl
griseophenone A
OH O OH O
OCH3 OCH3
O +2 [H] O
CH3 O O CH3 O O
CH3 CH3
Cl Cl
5. Polyketides
griseof ulv in
(Dayrit) dehy drogriseof ulv in
34
Nature of starting unit
Fatty acid synthase (FAS) Polyketide synthase (PKS)
O O O
O
C
C H3C SCoA OH SCoA
H3C SCoA Propionyl CoA
Acetyl CoA
Acetyl CoA
O Benzoyl CoA
O O O
O
C C OH
OH R1
HO CH2 SCoA SCoA
Butyryl CoA
Malonyl CoA Isobutyryl CoA
R2
O O R1 R2
O O
O Cinnamoyl CoA H H
C C p-Coumaroyl CoA H OH
HO CH SCoA
H3C SCoA Caffeoyl CoA OH OH
R OH
CH3 Hexanoyl CoA, R=C 5H11 Feruloyl CoA OH OMe
Acetoacetyl CoA
Methylmalonyl CoA Octanoyl CoA, R=C 7H15
O O O
MeHN
H2N SCoA SCoA
Acetamidoacetyl CoA
N-Methylanthranyloyl CoA
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 O OH
o o o o o
HO
o o o o
HO OH O OH
7S, 9R, 10R--pyrramycinine
Cl H C OH N(CH3)2
3
H
o o o o o OH
o o o o CONH2
CONH2
OH
OH O OH O
tetracycline
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.
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.
In microorganisms:
[O]
polyketide aromatic compound quinone
Overview of biosynthesis
In plants:
of quinones. Depending [O]
polyketide aromatic compound quinone
on the organism,
quinone
quinones can arise via shikimate aromatic compound
+ terpene
the polyketide or [O]
shikimate pathways. quinone

(mixed metabolite)
Aromatic metabolites in quinone from shikimate: quinones from shikimate + terpene:
OH OH O
microorganisms are likely H OH
to be formed via the CO2H
polyketide pathway while

OH OH O
aromatic compounds in homogentisic acid alkarinin
plants are likely to come O
from the shikimate R
pathway.
H
O 39 n
ubiquinones: R = H, CH3 ; n = 4-13

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 1,4-
benzoquinone.
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 OH
characteristic of plants. Arbutin
A. Plants store precursors of para-quinone in various glycosylated forms.
O-Glucose O-Glu-O-Glu O-Glu-O-Glu-O-Glu
Para-quinone is a toxic
compound which OH OH OH
arbutin
various organisms use.
A. Various trees secrete
a precursor (arbutin) to O
clear its surroundings
of competing plants; para-quinone
(toxic)
B. The bombardier
O
beetle produces para-
quinone in its collecting B. Para-quinone as a defensive secretion of the bombardier beetle.
bladder from para-
OH collecting bladder
hydroquinone + H2O2. lobe + H2 O2
explosion
OH
chamber with
enzyme gland
+ H2 O + heat
O
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
OCH3
aflatoxin B1
from Apergillus species
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.
[O] O
HO OH
o o o o
o o o o o o
decaketide OH O OH O O O
Aflatoxins +2[H] +2[H], -H 2O, +2[H]
make up a HO
O
O
O
H
+
HO OH O
family of HO
polyketide OH O OH OH
OH O OH OH
metabolites. -H2 O
O O
The very HO O
[O] HO OH
O
complex O
OH OH
biosynthesis OH O
averufin
OH
[O]
OH O OH
O-H
-H 2O
of aflatoxins O
O
was HO OH
CHO CHO
-C2
HO OH
O
O-H
elucidated
OH O OH CHO
by George OH O OH
Bchi. O O
O
HO O O HO O
OH O OH OH O OH
versicolorin A versicolorin B
5. Polyketides (Dayrit)
[O], Bayer-Villiger
46
O
+2[H]
HO O O [O] HO CO2H HO O O
Bayer-Villiger
OH O OH OH O OH
versicolorin A
+2[H],
-CO2
O
[O] H O
H HO O
O O
OH O OH
OH O OH
sterigmatocystin
[O]
H [O] H O H O
O
O H H HO2C H
O O
O O O O O
O
OH O OH O OH O O OH
OH
H O
H O
H O
-CO 2 , H
H O O O
H +[CH 3 ], O O O
O O O -H 2 O
O
O
O
OH _ O OH
OH
OCH3
5. Polyketides (Dayrit) CO2H 47
CO2H [CH 3 ]
aflatoxin B1
[O] O
HO OH
o o o o
o o o o o o
decaketide OH O OH O O O
+2[H] +2[H], -H 2O, +2[H]

O
O +
HO H
O
HO OH O
HO
OH O OH OH
OH O OH OH
-H2 O
O O
[O] HO OH
HO O O
OH OH
O
OH O OH OH O OH
O-H
averufin [O]
-H 2O
O O
O
HO HO OH
5. Polyketides
OH (Dayrit)
-C2 48
O-H
CHO CHO
OH O OH OH
OH O OH OH
-H2 O
O O
[O] HO OH
HO O O
OH OH
O
OH O OH OH O OH
O-H
averufin [O]
-H 2O
O O
O
HO HO OH
OH -C2 O-H
CHO CHO
OH O OH CHO
OH O OH
O O
HO O O HO O O
OH O OH OH O OH
versicolorin A versicolorin B
5. Polyketides
[O], Bayer-Villiger (Dayrit) 49
O
+2[H]
HO O O [O] HO CO2H HO O O
Bayer-Villiger
OH O OH OH O OH
versicolorin A
+2[H],
-CO2
O
[O] H O
H HO O
O O
OH O OH
OH O OH
sterigmatocystin
[O]
H [O] H O H O
O
O H H HO2C H
O O
O O O O O
O
OH O OH 5. PolyketidesOH
(Dayrit)
O OH O O 50
OH
O
[O] H O
H HO O
O O
OH O OH
OH O OH
sterigmatocystin
[O]
H [O] H O H O
O
O H H HO2C H
O O
O O O O O
O
OH O OH O OH O O OH
OH
H O
H O
H O
-CO 2 , H
H O O O
H +[CH 3 ], O O O
O O O -H 2 O
O
O
O
OH _ O OH
OH
OCH3
CO2H
5. Polyketides (Dayrit)
CO2H [CH 3 ] 51
aflatoxin B1
+2[H] [CH 3] [O]
CH3 OH
OH
o o o o o
NH2
o o o o CONH2
HO HO OH OH O [O]
CH3 H O CH3 O
H
OH OH
NH2 NH2
Biosynthesis of +H 2O
HO HO O O O HO HO OH O O
tetracyclines from CH3 O CH3

H
O
H
OH
Streptomyces OH
NH2 NH2
species. OH OH
HO HO O O O HO HO O O O
+2[H]
CH3 OH
CH3 N(CH3)2
H
H +[NH2 ], OH
OH +2[CH3 ]
NH2
NH2
OH
OH
HO HO O O O
HO HO O O O
[Cl]
Cl CH3 N(CH3)2
H
OH
H3C OH R N(CH3)2
H
NH2 OH
OH A B C D
HO HO O O O
CONH2
OH
OH O OH O
Cl H C N(CH3)2 R=H : tetracycline

3 OH
H R=OH : terramycin
OH
A B C D aureomycin
OH
5. Polyketides
CONH (Dayrit)
2 52
OH O OH O
+2[H] [CH 3] [O]
CH3 OH
OH
o o o o o
NH2
o o o o CONH2
HO HO OH OH O [O]
CH3 H O CH3 O
H
Biosynthesis of OH
OH
tetracyclines
NH2
from NH2
Streptomyces HO HO O O O HO HO OH O O
+H 2O
species.
CH3 O CH3 O
H H
OH OH
NH2 NH2
OH OH
+2[H]
CH3 OH
CH3 N(CH3)2
H
H +[NH2 ], OH
OH +2[CH3 ]
NH2
NH2
OH
OH
HO HO O O O
HO HO O O O
Cl CH3
5. Polyketides
N(CH3)2
[Cl] (Dayrit) 53
H
OH
HO HO O O O
+H 2O
CH3 O CH3 O
H H
OH OH
NH2 NH2
OH OH
+2[H]
CH3 OH
CH3 N(CH3)2
H
H +[NH2 ], OH
OH +2[CH3 ]
NH2
NH2
OH
OH
HO HO O O O
HO HO O O O
[Cl]
Cl CH3 N(CH3)2
H
OH
H3C OH R N(CH3)2
H
NH2 OH
OH A B C D
HO HO O O O
CONH2
OH
OH O OH O
Cl H C N(CH3)2 R=H : tetracycline

3 OH
H R=OH : terramycin
OH
A B C D aureomycin
CONH2
OH 5. Polyketides (Dayrit) 54
OH O OH O
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.
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.

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5.

The polyketides have great diversity of structures and

4x C _ The elucidation of the

Variations in number of C2 units and mode of cyclization

A. Colletodiol; B. Use of labeling experiment to distinguish inter- vs. intramolecular cyclization.

(from: The World of Polyketides, http://linux1.nii.res.in/)

(from: The World of Polyketides, http://linux1.nii.res.in/)

Predicted domain organization of the 6-deoxyerythronolide B synthase (DEBS) proteins.

Inactivation of KR5 of DEBS results in the production of erythromycin analogues with

Inactivation of ER4 results in an analogue of erythromycin with a double bond at the

The PKS system is likely derived from bacterial FAS. Different

KS: ketoacyl synthase

Organization of fatty acid synthases (FAS) and polyketide

Enzymes in a PKS module.

KS: ketoacyl synthase

common aromatic intermediate principal common intermediate

Four proteins comprise the minimal PKS: ketosynthase (KS),

OH O OH CH3 OH O OH CH3 OH O OH CH3

Tcm B3 Tcm D3 Tcm F1

The optimal Tcm PKS is a complex consisting of the TcmJKLMN proteins. It is

Modification Before cyclization After cyclization

The various Kingdoms exhibit different characteristics of their PKS

was first marketed

+[CH3 ] griseophenone B griseophenone C

OCH3 O OCH OH O OCH OH O OCH

7S, 9R, 10R--pyrramycinine

The polyketide metabolites can be classified into five groups:

shikimate pathways. quinone

Aromatic metabolites in quinone from shikimate: quinones from shikimate + terpene:

to be formed via the CO2H

polyketide pathway while

from the shikimate R

ubiquinones: R = H, CH3 ; n = 4-13

O-Glucose O-Glu-O-Glu O-Glu-O-Glu-O-Glu

Aflatoxins +2[H] +2[H], -H 2O, +2[H]

+2[H] +2[H], -H 2O, +2[H]

tetracyclines from CH3 O CH3

Cl H C N(CH3)2 R=H : tetracycline

Cl H C N(CH3)2 R=H : tetracycline

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