5. Polyketides RA Macahig FM Dayrit. 5. Polyketides (Dayrit)2 Polyketides rank among the largest group of secondary metabolites in terms of diversity.

5. Polyketides5. 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

alternariolfrom the mould Alternaria tenius

OH3C

O

OOCH3

CH3O

Cl

OCH3

griseofulvinfrom Penicillium griseofulvum

O O

O

O

O

OCH3

aflatoxin B1from Apergillus species

O

O

OH

CH3

ORCH3

OR

CH3

O

H3C

HO

H3C CH3

macrolide antibioticerythromycin-typefrom 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 5 4 3 2 1

Claisen6 1

b

Aldol2 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

OS-CoA

O

OO

O O

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


Starting polyketide Secondary metabolite

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

Variations in number of C2 units and mode of cyclization

hexaketide:

oo

oo

o o

O OH

CH3CH3O

OH O

diaporthin(Endothia parasitica)


Starting polyketide Secondary metabolite

monocerin(Helminthosporium

monoceras)

oo

o o

o o

heptaketide:

o

O

CH3O

OH O

O

CH3O

oo

o o o

oogriseofulvin(Penicillium

griseofulvum)OH3C

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 oCH3HO

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 o OH

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

OO

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: -keto acyl synthase• MAT: malonyl (acyl) transferase• DH: dehydratase• ER: enoyl reductase• KR: keto reductase• TE: thiol esterase(from: The World of Polyketides, http://linux1.nii.res.in/)

H3C

O

O

CH3 CH3

O

O OH

Lovastatin

CO2H

H3C OH

6-Methylsalicylic acid

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: ketoreductaseACP: acyl carrier protein


Biosynthesis of macrolides on a modular Polyketide Synthase (PKS) multienzyme complex.

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


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: ketoreductaseACP: acyl carrier proteinTE: 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: ketoreductaseACP: acyl carrier proteinTE: 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 proteinTE: 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)


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 synthaseAT: acyl transferaseDH: dehydrataseER: enoyl reductaseACP: 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 synthaseACP: acyl carrying proteinKR: ketoreductaseDH: dehydrataseER: 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 intermediatewith varying R group

Common enzymes in aromatic polyketides


“Deciphering the mechanism for the assembly of aromaticpolyketides 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. NADPH2. -H O2

S-CoA

O

O_

S-CoA

O

O2C

O

O

S-CoA

O

o

o

o

CH3

CO2H

OH

6-methylsalicylic acidfrom 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

HO2-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.

S-CoA

O

S-CoA

CO2H

O

*

*

starter unit

+ 6

oo

o

oo

o

o

13

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

C H3 O O

OCH3

O

C H3C l

+2 [H]

dehydrogriseofulvin

OOH

C H3 O O

OCH3

O

C H3C l

OOH

C H3 O O

OCH3

O

C H3C l

...

.

OOH

C H3 O O

OCH3

O

C H3C l

[O]

3+[CH ]

griseophenone A

OOCH3

C H3 O OH

OCH3

OH

C H3C l

+[Cl], -[H]

OOH

C H3 O OH

OCH3

OH

C H3C l

griseophenone B griseophenone C

OOH

C H3 O OH

OCH3

OH

C H3

3+2 [CH ]

OOH

H O OH

OH

OH

C H3

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. Quinones3. Aflatoxins4. Tetracyclines5. 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.


39

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 withenzyme 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

OH

+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

HOCHO 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

OH

+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

HOCHO CHO

OHO

O

OH

HO O O

versicolorin A

[O], Bayer-Villiger

versicolorin B

OHO

O

OH

HO O O


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

OH

+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

HOCHO 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


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 : tetracyclineR=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]



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.



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

5. Polyketides RA Macahig FM Dayrit. 5. Polyketides (Dayrit)2 Polyketides rank among the largest group of secondary metabolites in terms of diversity.

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