Category:PK

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{{Huge|Polyketide (ポリケチド)}}
 
{{Huge|Polyketide (ポリケチド)}}
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{| style="float:right"
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| __TOC__
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|}
  
 
==Class Overview==
 
==Class Overview==
  
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{{Twocolumn|
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Polyketides are synthesized through the polymerization of acetyl units (β-ketomethylene chain).
 +
The key reactions for chain extensions are:
 +
* Claisen condensation by β-ketoacyl synthase ('''KS''')
 +
* an acyltransferase ('''AT'''), and
 +
* an acyl carrier protein ('''ACP''').
 +
After elongation, key reactions in synthesis are:
 +
* reduction to an alcohol by ketoreductase ('''KR'''),
 +
* dehydration to the conjugated ester by dehydratase ('''DH'''), and
 +
* reduction of the double bond by enoyl reductase ('''ER''').
 +
Finally, the chain is terminated by a thioesterase ('''TE''') activity and
 +
allows cyclization (lactonization).
 +
|
 +
ポリケチドはアセチル単位 (β-ケトメチレン鎖) の重合によって作られます。
 +
鎖の伸長に使う反応は
 +
* β-ケトアシル合成酵素 ('''KS''') によるクライゼン縮合
 +
* アシル基転移酵素 ('''AT''') による伸長と、それを支える
 +
* アシル輸送タンパク質 ('''ACP''')
 +
です。また、伸張後に重要な反応は
 +
* ケト還元酵素 ('''KR''') によるアルコールへの還元
 +
* 脱水酵素 ('''DH''') による共役エステルからの脱水
 +
*  エノイル還元酵素 ('''ER''') による二重結合の還元
 +
です。最後に、チオエステル分解酵素 ('''TE''') によって伸張が止まり、ラクトン化 (閉環) します。
 +
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---->
 
---->
  
−
{{Twocolumn|
 
−
Polyketides are synthesized through the polymerization of acetyl units (β-ketomethylene chain).
 
−
The key reactions for chain extensions are:
 
−
* Claisen condensation by β-ketoacyl synthase ('''KS''')
 
−
* an acyltransferase ('''AT'''), and
 
−
* an acyl carrier protein ('''ACP''').
 
−
After elongation, key reactions in synthesis are:
 
−
* reduction to an alcohol by ketoreductase ('''KR'''),
 
−
* dehydration to the conjugated ester by dehydratase ('''DH'''), and
 
−
* reduction of the double bond by enoyl reductase ('''ER''').
 
−
Finally, the chain is terminated by a thioesterase ('''TE''') activity and
 
−
allows cyclization (lactonization).
 
−
|
 
−
ポリケチドはアセチル単位 (β-ケトメチレン鎖) の重合によって作られます。
 
−
鎖の伸長に使う反応は
 
−
* β-ケトアシル合成酵素 ('''KS''') によるクライゼン縮合
 
−
* アシル基転移酵素 ('''AT''') による伸長と、それを支える
 
−
* アシル輸送タンパク質 ('''ACP''')
 
−
です。また、伸張後に重要な反応は
 
−
* ケト還元酵素 ('''KR''') によるアルコールへの還元
 
−
* 脱水酵素 ('''DH''') による共役エステルからの脱水
 
−
*  エノイル還元酵素 ('''ER''') による二重結合の還元
 
−
です。最後に、チオエステル分解酵素 ('''TE''') によって伸張が止まり、ラクトン化 (閉環) します。
 
−
}}
 
  
 
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{| class="wikitable"
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|-
 
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|  
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{| class="collapsible collapsed"  
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{| class="collapsible collapsed" style="width:150px"
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! Linear polyketides
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! Linear
 
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|-
 
| linear
 
| linear
 
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|  
 
|  
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{| class="collapsible collapsed"
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{| class="collapsible collapsed" style="width:150px"
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! Polyether polyketides
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! Polyether
 
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| nigericin
 
| nigericin
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| Acetogenins
 
| Acetogenins
 
|
 
|
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{| class="collapsible collapsed"  
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{| class="collapsible collapsed" style="width:150px"
 
! Cyclic imines
 
! Cyclic imines
 
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|-
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|-
 
|-
 
|  
 
|  
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{| class="collapsible collapsed"  
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{| class="collapsible collapsed" style="width:150px"
 
! with Benzene
 
! with Benzene
 
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|
 
|
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{| class="collapsible collapsed" style="width:150px"
 
! Tetracycline
 
! Tetracycline
 
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!colspan="4"| Macrolides (most often by non-iterative type I)
 
!colspan="4"| Macrolides (most often by non-iterative type I)
 
|-
 
|-
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| Polyene Type
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|style="width:150px"| Polyene Type
 
* Manumycin
 
* Manumycin
 
* Nystatin
 
* Nystatin
 
* Amphotericin
 
* Amphotericin
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| Macrolides
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|style="width:150px"| Macrolides
 
* Ansamycin
 
* Ansamycin
 
* Avermectin (16-membered), Milbemycin (20-membered)
 
* Avermectin (16-membered), Milbemycin (20-membered)

Revision as of 18:52, 16 December 2010

Polyketide (ポリケチド)

Contents

Class Overview

Polyketides are synthesized through the polymerization of acetyl units (β-ketomethylene chain). The key reactions for chain extensions are:

  • Claisen condensation by β-ketoacyl synthase (KS)
  • an acyltransferase (AT), and
  • an acyl carrier protein (ACP).
After elongation, key reactions in synthesis are:
  • reduction to an alcohol by ketoreductase (KR),
  • dehydration to the conjugated ester by dehydratase (DH), and
  • reduction of the double bond by enoyl reductase (ER).
Finally, the chain is terminated by a thioesterase (TE) activity and allows cyclization (lactonization).


Table 1. Polyketide Classification
1st Class
PK4: Four C2 Units

orsellinic acid, 6-methylsalicylic acid, triacetic acid lactone, asperlin, usnic acid, methylphloracetophenone, penicillic acid, patulin

PK5: Five C2 Units

citrinin, aflatoxin, augenone, sepedonin, stipitatonic acid

PK6: Six C2 Units

plumbagin, 7-methyljuglone, juglone, variotin

PK7: Seven and eight C2 Units

Anthraquinone rings
griseofulvin, rubrofusarin, emodin, alizarin, pachybasin, xanthone, versicolorin A, aflatoxin B1, sterigmatocystin, tajixanthone

PK9: Nine C2 Units

Tetracyclines
terramycin, aureomycin, daunomycin


Extent of Reduction
fully reduced partially reduced unreduced
fatty acids, linear PKs macrolides aromatics
Linear Chain and Related
Acetogenins
Aromatic and Related
Macrolides (most often by non-iterative type I)
Polyene Type
  • Manumycin
  • Nystatin
  • Amphotericin
Macrolides
  • Ansamycin
  • Avermectin (16-membered), Milbemycin (20-membered)
  • Bafilomycin (16-membered)
  • Bryostatin (26-membered. lacks AT domain as in mupirocin, leinamycin[1])
  • Colletodiol (14-membered)
  • Cytovaricin
  • Erythromycin (14-membered) 6-deoxy sugars (L-cladinose and D-desosamine) are attached.
  • Fluvirucin (14-membered)
  • Myxovirescin (28-membered http://www.indiana.edu/~drwchem/pdfs/50.pdf)
  • Nonactin, Nactin
  • Natamycin (26-membered =Pimaricin)
  • Oligomycin (16-membered)
  • Tacrolimus (23-membered =FK-506 or Fujimycin)
  • Tylosin (16-memberd)

Polyketide Synthase (PKS)

species Actinomycetes Cyanobacteria γ-Proteobacteria Fungi Dinoflagellates
Type-I PKS Ο Ο Ο Χ Ο
Type-II PKS Ο Χ Χ Ο Χ
NRPS Ο Ο Ο Ο Χ
deoxysugar Ο Χ Χ Χ Χ
Terpene Δ Χ Χ Ο Χ

Type I PKS (non-iterative)

  • Multi catalytic domains exist in a single protein
  • Chain length is determined by the number of catalytic domains.
  • Products are non-aromatic and have larger masses.

Ref. Erythromycin biosynthesis in Nat Prod Rep 18, 380 (2001)

Type II PKS (iterative)

  • Three proteins (KSα, KSβ, ACP) are repeatedly used for carbon chain elongation.
  • Chain length is determined by another protein, CLF.
  • In bacteria, products are aromatic (e.g. chiorotetracycline, pradimicin).
  • In fungi, products are both non-aromatic and aromatic.

Non-ribosomal peptide synthase (NRPS)

Coupling with PKS and NRPS

  • vancomycin ()
  • leinamycin (Curr opin chem biol 7:285, 2003)
  • pseurotin (chem bio chem 8:1736-1743, 2007)
  • curacin (curr opin chem biol 13:216, 2009)
  • epothilone
  • rapamycin

PKS in Fungi

  • both aromatic and non-aromatic compounds are generated by iterative PKS
  • methyl branch is transferred from methionine, not methylmalonyl CoA

Ref. Dewick, PM Medicinal Natural Products (2009)


Decoration

deoxysugars

deoxygenation, c-methylation, amination, n-methylation, ketosugar,

Unusual structures

Phoma zaragozic acid, phomoidoride Streptomyces yatakemycin, leinamycin, saframycin, neocarzinostatin, staurosporin, FR182877 Other bacteria PKS-NRPS hybrid type

Curacin A (Lyngbya), Shiphonazole (Herpetosiphon), Jamaicamide A (Lyngbya), Cylindrospermopsin (Cylindrospermopsis)



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Subcategories

This category has only the following subcategory.

P

  • [×] PKS‎ (empty)
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