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5. Polyketides

RA Macahig

FM Dayrit

5. Polyketides (Dayrit) 2

• 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.

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.


Examples of polyketide natural products which illustrate

the wide variety of structures which comprise this group.

CH3

CO2H

OHHO

orsellinic acid

O

HO

O

OH

OH

alternariol

from the mould Alternaria tenius

O

H3C

O

OOCH3

CH3O

Cl

OCH3

griseofulvin

from Penicillium griseofulvum

O O

O

O

O

OCH3

aflatoxin B1

from Apergillus species

O

O

OH

CH3

ORCH3

OR

CH3

O

H3C

HO

H3C CH3

macrolide antibiotic

erythromycin-type

from Streptomyces species


• 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.

Introduction

• 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).


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:

Overview of polyketide biosynthesis

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.


S-CoAC

CH2

CCH2

CCH2

CH3C

OOOO

a ab b

c cdd

a

87

6 54

32 1

Claisen

6 1

b

Aldol

2 7

cd

C

CH3

O

OHHO

OH

xanthoxylin

(a phloroglucinol)

CH3

CO2H

OHHO

(8)

(1)

(8)

(1)

orsellinic acid

(a resorcinol)

O

HO O

CH2

C

CH3

O

(an -pyrone)

O

O

H3C CH2CO2H

(1)

(1)

(8)

(8)

(a -pyrone)

O

O

O

S-CoA

O

S-CoA

O

OO

OO

O

S-CoAO

O O S-CoA

O

O

O

Aromatic

polyketides. Major

cyclization pathways

for a tetraketide

followed by

aromatization.


Biosynthetic studies on polyketides (Arthur Birch)

4 x H3C

CO

O

_

*

*#

ratio: 14C # 1

--------- = ----

18O * 2

S-CoA

O O O O* * * *

# # # #

# 1

------ = ----

* 1

O O

OH

S-CoA

O

* *

**

#

#

#

#-H O*2#

#

#

#

*

**HO OH

CH3O

OH

# 4

------ = ----

* 3

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.


Birch proposal for polyketide biosynthesis:

Overview of 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.


Variations in number of C2 units and mode of cyclization

Starting polyketide Secondary metabolite

O

HO

O

triketide:

o

o

o

tetraketides:

o

oo

o

oo

o o

CH3

CO2H

OHHO

orsellinic acid

(1)

xanthoxylin(1)

OH

CH3

O

OHHO

Short-hand

representation of

polyketides:

CH3

S-CoAO

O

O O

a tetraketide

o

o o

=

o



OH

CH3

O

HOCO2H(1)

curvulinic acid

(Curvularia siddiqui)

(1) O

O

CH3HO

OH

oo

o o

o

o o

o

pentaketides:

o

o

OH O

OHO CH3(1)

o

o

o

o

o


hexaketide:

oo

oo

o o

O OH

CH3CH3O

OH O

diaporthin

(Endothia parasitica)



monocerin

(Helminthosporium

monoceras)

oo

o o

o o

heptaketide:

o

O

CH3O

OH O

O

CH3O

oo

o o o

oo

griseofulvin

(Penicillium

griseofulvum)O

H3C

O

OOCH3

CH3O

Cl

OCH3

o

o

o

o

o

o

o

O

CH3

OH

O

HO

HO

alternariol

(Alternaria tenius)



Starting polyketide Secondary metaboliteoctaketide:

oo

oo

o o

CH3HO

OH O

O

CO2H

endocrocin

(Centralia endocrocea)

o o

oo

oo

o o

o

o

O

HO

HO

O

O

curvularin

(Curvularia spp.))


nonaketide:

o

o

oo

o o

O

O

HO

Cl

OCH3

O

HO

radiciciol

(Nectaria radiciola)

o o

o

ooooo

o o o oOH

CH3

O

O

CH3O

HO OH

nalgiovensin

(Penicillium

nalgiovensis)


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

O

OHOH

colletodiol

A. Example of intermolecular cyclization.

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

o

ooo

oo

o

o o o o

oooo

[Me*]

OH OH O

*-CO2

2-2CO


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

Biosynthesis of

macrolides:

Step-wise

chemical

transformations

and enzymes.


Hypothetical

scheme of the

biosynthesis of

phenol

polyketides

on the

Polyketide

Synthase

(PKS)

multienzyme

complex.

multi-enzyme complex

HS HS HS HS HS H3C S-CoA

O

S

O

HSHSHSHSS-CoA

O

O2C

_

4 x

S

O2C

O

S

O

__

S

O2C

O

_

S

O2C

O

__

S

O2C

O

S

O2C

O

__

S

O2C

O

_

S

O2C

O

_

S

O

o

HS

*

*

*

HSHSHSHSS

O

O

O

*

O

o

S

O

O

O

O

O

_

base_

SO

O

O

OH

O

HO

OH

CO2H

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.

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.

• ACP: acyl carrying protein

• KS: b-keto acyl synthase

• MAT: malonyl (acyl) transferase

• DH: dehydratase

• ER: enoyl reductase

• KR: keto reductase

• TE: thiol esterase


H3C

O

O

CH3 CH3

O

O OH

Lovastatin

CO2H

H3C OH

6-Methylsalicylic acid


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)


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)

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)

KS: ketosynthase

AT: acyltransferase

DH: dehydratase

ER: enoyl reductase

KR: ketoreductase


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, 380–416)

KS: ketosynthase AT: acyltransferase DH: dehydratase

ER: enoyl reductase KR: ketoreductase ACP: acyl carrier protein

TE: thioesterase


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)

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

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)

KS: ketosynthase

MAT: malonyl-acetyl transferase

DH: dehydratase

KR: ketoreductase



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?

Enzymes in a PKS module. (Jenke-Kodama et al. J Mol Bio

Evol 2005)

Common sequence of reactions performed by FAS and PKS.

KS: ketoacyl synthase

ACP: acyl carrying protein

KR: ketoreductase

DH: dehydratase

ER: enoyl reductase


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)

-O2C

S-CoA

O

starter unit

min PKS

R

O

OO

O

O O O

SACP

OKS-CLF

R

O

OO

O

O O

SACP

O

OH

15

9

C-9 KR

9

R

O

OO

HO

O O

SACP

O

OH

ARO

R

O

OOH

O O

SACP

OCYC

R

O

OOH

O

S-ACP

O5

common aromatic intermediate principal common intermediate

with varying R group

Common enzymes in aromatic polyketides


“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.

Acyl-CoA +9 Mal-CoA

TcmJKLM

CH3

O

OOO

O

O O O

O

SCoA

OTcmN

unidentified productsaberrantcyclization

CH3

CO2HO

OH

OHOHOH

HO

Tcm F2

Tcm F1

CH3

CO2H

OH

OHOOH

HO

TcmI

TcmH

CH3

CO2H

OH

OHOOH

HO

O

Tcm D3Tcm B3

CH3

CO2H

OH

OHOOH

CH3O

O

TcmN

Tetracenomycin PKS J K L M N

7 kb0

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.

S-CoA

O

+ 2 x S-CoA

O

O2C_

S-CoA

O O O

1. NADPH

2. -H O2

S-CoA

O

O_

S-CoA

O

O2C

O

O

S-CoA

O

o

o

o

CH3

CO2H

OH

6-methylsalicylic acid

from Penicillium urticae


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.

oo

o o

[CH ]3

3[CH ]

CH3

OH

H3C

HO

CH3

O

clavatol

CH3

OH

HO

O

CH3

OH

H3C

HO

O


Secondary processes: examples of oxidation, decarboxylation and methylation.

6-methylsalicylic acid

CH3

CO2H

OH

[O]

CHO

CO2H

OH

-CO2

CHO

OH

CO2H

OH

HO

[O]

gentisic acid

A. Gentisic acid

B. Fumigatin

fumigatin

[CH ]

CH3

OH

OCH3

HO

HO

2-CO

CH3

OHHO

1. [O]

2.

CH3

CO2H

OHHO

orsellinic acid

3 [O]

CH3

O

OCH3

HO

O


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 gram-

positive bacterial

infections.

(from Wikipedia)

S-CoA

O

S-CoA

CO2H

O

*

*

starter unit

+ 6

oo

o

oo

o

o

1

3

5

79

11

13

O

O

O

OHHO

OR3

OR2

OR1

*

1 3

5

7

9

11

13

Erythromycin R1 R2 R3

A OH 1 2

B H 1 2

C OH 1 3

1 : D-desosamine:

2 : L-cladinosine:

3 : L-mycarose:

O

CH3

N(CH3)2

OH

OHO

CH3

CH3

CH3

OHO

CH3

CH3

OH


Intramolecular aromatic radical coupling: biosynthesis of griseofulvin (from a fungus, Penicilliumgriseofulvum) involves extensive secondary modification of a heptaketide.

griseofulvin

OOH

CH3O O

OCH3

O

CH3

Cl

+2 [H]

dehydrogriseofulvin

OOH

CH3O O

OCH3

O

CH3

Cl

OOH

CH3O O

OCH3

O

CH3Cl

...

.

OOH

CH3O O

OCH3

O

CH3Cl

[O]

3+[CH ]

griseophenone A

OOCH3

CH3O OH

OCH3

OH

CH3Cl

+[Cl], -[H]

OOH

CH3O OH

OCH3

OH

CH3Cl

griseophenone B griseophenone C

OOH

CH3O OH

OCH3

OH

CH3

3+2 [CH ]

OOH

HO OH

OH

OH

CH3

o o

ooo

o o


Nature of starting unit

Fatty acid synthase (FAS)

H3CC

SCoA

O

Acetyl CoA

Malonyl CoA

CH2

CSCoA

O

CHO

O

CHC

SCoA

O

CHO

O

CH3

Methylmalonyl CoA

Polyketide synthase (PKS)

Isobutyryl CoA

SCoA

O

H3C

O

Acetoacetyl CoA

Acetyl CoA

H3CC

SCoA

O

Hexanoyl CoA, R=C5H11

Octanoyl CoA, R=C7H15

OH

O

OH

O

Propionyl CoA

Butyryl CoAOH

O

SCoA

O

Benzoyl CoA

R1 R2Cinnamoyl CoA H Hp-Coumaroyl CoA H OHCaffeoyl CoA OH OHFeruloyl CoA OH OMe

SCoA

O

R1

R2

N-Methylanthranyloyl CoA

SCoA

O

MeHN

R OH

O

Acetamidoacetyl CoA

SCoA

O

H2N

O


Nature of starting unit

Examples of metabolites where the starting unit is not acetyl-CoA. In the case of tetracycline, extensivesecondary processes take place.

o

o o o o

oooo

o

HO

CO2H

HO OH O

O OH

OH

7S, 9R, 10R--pyrramycinine

CONH2

oooo

o o o o

o

Cl

OH O OH O

CONH2

OH

OHH3C

OH

HN(CH3)2

tetracycline


The polyketide metabolites can be classified into five groups:

1. Phenols

2. Quinones

3. Aflatoxins

4. Tetracyclines

5. Macrolide antibiotics

Metabolites from polyketides

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.

Aromatic compounds


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.


38

Overview of biosynthesis

of quinones. Depending

on the organism,

quinones can arise via

the polyketide or

shikimate pathways.

In microorganisms:

[O]

polyketide aromatic compound quinone

In plants:

[O]

polyketide aromatic compound quinone

shikimate aromatic compound + terpene

[O]

quinone

(mixed metabolite)

quinone

OH

CO2H

OH

OH

OH

O

O

OHH

quinones from shikimate + terpene: quinone from shikimate:

homogentisic acid alkarinin

R

O

O

H

n

ubiquinones: R = H, CH ; n = 4-133

• 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.


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

OH

Arbutin

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.


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 para-

quinone in its collecting

bladder from para-

hydroquinone + H2O2.

A. Plants store precursors of para-quinone in various glycosylated forms.

O-Glucose

OH

arbutin

O-Glu-O-Glu

OH

O-Glu-O-Glu-O-Glu

OH

O

O

para-quinone

(toxic)

B. Para-quinone as a defensive secretion of the bombardier beetle.

lobe

O

O

+ H O2 2

collecting bladder

explosion

chamber with

enzyme gland

OH

OH

+ H O + heat2


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

aflatoxin B1from 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.



ooo

o o o o

o o o

decaketide

[O]

HO

OH

O

O OH

OH

O O O

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

HO

OH

O

O OH

OH

OH

O

H+

HO

OH

O

O OH

O

OH

HO

HO

OH

O

O OH

O

O

-H O2

averufin [O]

[O] HO

OH

O

O OH

OH

OH

O - H

OH

O

-H O2

O - H

OOH

OHO

O

OH

HO

CHO

-C2OH

OHO

O

OH

HO

CHO CHO

OHO

O

OH

HO O O

versicolorin A

[O], Bayer-Villiger

versicolorin B

OHO

O

OH

HO O O

Aflatoxins

make up a

family of

polyketide

metabolites.

The very

complex

biosynthesis

of aflatoxins

was

elucidated

by George

Büchi.


versicolorin A

OHO

O

OH

HO O O [O]

Bayer-Villiger

OHOOH

HO O OCO2H HO

+2[H]

+2[H],

-CO2

OHOOH

HO O

O

OHOOH

O O

O

H

H

sterigmatocystin

OHOOH

O O

O

H

H

O

[O]

OHOOH

O O

O

H

H

O

[O]

[O]

OHOO

HO2CO O

O

H

H

O

OHO

O O

O

H

H

O

CO2H

O

_OH

OH

O O

O

H

H

O

CO2H

O

[CH ]3

-CO ,

+[CH ],

-H O

2

2

3

OCH3

O O

O

H

H

O

O

aflatoxin B1


ooo

o o o o

o o o

decaketide

[O]

HO

OH

O

O OH

OH

O O O

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

HO

OH

O

O OH

OH

OH

O

H+

HO

OH

O

O OH

O

OH

HO

HO

OH

O

O OH

O

O

-H O2

averufin [O]

[O] HO

OH

O

O OH

OH

OH

O - H

OH

O

-H O2

O - H

OOH

OHO

O

OH

HO

CHO

-C2OH

OHO

O

OH

HO

CHO CHO

OHO

O

OH

HO O O

versicolorin A

[O], Bayer-Villiger

versicolorin B

OHO

O

OH

HO O O


versicolorin A

OHO

O

OH

HO O O [O]

Bayer-Villiger

OHOOH

HO O OCO2H HO

+2[H]

+2[H],

-CO2

OHOOH

HO O

O

OHOOH

O O

O

H

H

sterigmatocystin

OHOOH

O O

O

H

H

O

[O]

OHOOH

O O

O

H

H

O

[O]

[O]

OHOO

HO2CO O

O

H

H

O

OHO

O O

O

H

H

O

CO2H

O

_OH

OH

O O

O

H

H

O

CO2H

O

[CH ]3

-CO ,

+[CH ],

-H O

2

2

3

OCH3

O O

O

H

H

O

O

aflatoxin B1


Biosynthesis of

tetracyclines from

Streptomyces

species.

R=H : tetracycline

R=OH : terramycin

OH O OH O

CONH2

OH

OHH3C

OH

HN(CH3)2R

o

oooo

o o o o

+2[H] [CH ] [O]

CONH2

3

NH2

OH

HO

CH3

HO OH OH O

OH

[O]

NH2

OH

HO

CH3

HO OH O O

O

NH2

OH

HO

CH3

HO O O O

OH H

NH2

OH

HO

CH3

HO O O O

OH

OH

+H O2

NH2

OH

HO

CH3

HO O O O

OH

OH

+2[H]

NH2

OH

HO

CH3

HO O O O

H

OH

OH

+[NH ],

+2[CH ]2

3

NH2

OH

HO

CH3

HO O O O

H

OH

N(CH3)2

A B C D

NH2

OH

HO

CH3

HO O O O

H

OH

N(CH3)2Cl

DCBA

Cl

OH O OH O

CONH2

OH

OHH3C

OH

HN(CH3)2

aureomycin

[Cl]


R=H : tetracycline

R=OH : terramycin

OH O OH O

CONH2

OH

OHH3C

OH

HN(CH3)2R

o

oooo

o o o o

+2[H] [CH ] [O]

CONH2

3

NH2

OH

HO

CH3

HO OH OH O

OH

[O]

NH2

OH

HO

CH3

HO OH O O

O

NH2

OH

HO

CH3

HO O O O

OH H

NH2

OH

HO

CH3

HO O O O

OH

OH

+H O2

NH2

OH

HO

CH3

HO O O O

OH

OH

+2[H]

NH2

OH

HO

CH3

HO O O O

H

OH

OH

+[NH ],

+2[CH ]2

3

NH2

OH

HO

CH3

HO O O O

H

OH

N(CH3)2

A B C D

NH2

OH

HO

CH3

HO O O O

H

OH

N(CH3)2Cl

DCBA

Cl

OH O OH O

CONH2

OH

OHH3C

OH

HN(CH3)2

aureomycin

[Cl]

Biosynthesis of

tetracyclines

from

Streptomyces

species.


R=H : tetracycline

R=OH : terramycin

OH O OH O

CONH2

OH

OHH3C

OH

HN(CH3)2R

o

oooo

o o o o

+2[H] [CH ] [O]

CONH2

3

NH2

OH

HO

CH3

HO OH OH O

OH

[O]

NH2

OH

HO

CH3

HO OH O O

O

NH2

OH

HO

CH3

HO O O O

OH H

NH2

OH

HO

CH3

HO O O O

OH

OH

+H O2

NH2

OH

HO

CH3

HO O O O

OH

OH

+2[H]

NH2

OH

HO

CH3

HO O O O

H

OH

OH

+[NH ],

+2[CH ]2

3

NH2

OH

HO

CH3

HO O O O

H

OH

N(CH3)2

A B C D

NH2

OH

HO

CH3

HO O O O

H

OH

N(CH3)2Cl

DCBA

Cl

OH O OH O

CONH2

OH

OHH3C

OH

HN(CH3)2

aureomycin

[Cl]


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.

Summary

1. introduction to natural products chemistry · ra macahig fm dayrit . 5. polyketides (dayrit) 2...

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