Category:PK

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{{Twocolumn|
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Polyketides are synthesized through the polymerization of acetyl units (β-ketomethylene chain).
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Polyketides are synthesized through the polymerization of acetyl units (β-ketomethylene) as in fatty acid  biosynthesis. Typical starter units are short-chain fatty acids (e.g. acetyl-CoA or propionyl-CoA), on to which extender units (e.g. malonyl-CoA or methylmalonyl-CoA) are repeatedly polymerized.
−
The key reactions for chain extensions are:
+
The key reactions for the chain extension are:
 
* Claisen condensation by β-ketoacyl synthase ('''KS''')
 
* Claisen condensation by β-ketoacyl synthase ('''KS''')
 
* an acyltransferase ('''AT'''), and
 
* an acyltransferase ('''AT'''), and
 
* an acyl carrier protein ('''ACP''').
 
* an acyl carrier protein ('''ACP''').
−
After elongation, key reactions in synthesis are:
+
 
−
* reduction to an alcohol by ketoreductase ('''KR'''),
+
After elongation, β-ketone is reduced.  In fatty acid biosynthesis, the chain is fully reduced by the following three steps:
−
* dehydration to the conjugated ester by dehydratase ('''DH'''), and
+
* Reduction to an alcohol by ketoreductase ('''KR'''),
−
* reduction of the double bond by enoyl reductase ('''ER''').
+
* Dehydration to the conjugated ester by dehydratase ('''DH'''), and
 +
* Reduction of the double bond by enoyl reductase ('''ER''').
 +
In polyketide synthase, the reduction is patial.
 +
 
 
Finally, the chain is terminated by a thioesterase ('''TE''') activity and
 
Finally, the chain is terminated by a thioesterase ('''TE''') activity and
−
allows cyclization (lactonization).
+
allows Claisen cyclization ('''CYC''').
 
|
 
|
 
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。
 
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。
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* アシル基転移酵素 ('''AT''') による伸長と、それを支える
 
* 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''')  
 
* 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
+
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
 
* 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
 
* 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
 
*  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。
+
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。
 +
}}
  
 
<center>
 
<center>
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{| class="wikitable"
 
{| class="wikitable"
−
!colspan="3" align="center"| Extent of Reduction
+
!colspan="4"| Linear Chain and Related ()
−
|-
+
−
| ''fully reduced'' || ''partially reduced'' || ''unreduced''
+
−
|-
+
−
| fatty acids, linear PKs || macrolides || aromatics
+
−
|}
+
−
 
+
−
{| class="wikitable"
+
−
!colspan="4"| Linear Chain and Related
+
 
|-
 
|-
 
|  
 
|  
 
{| class="collapsible collapsed" style="width:150px"
 
{| class="collapsible collapsed" style="width:150px"
−
! Linear
+
! Straight (LS)
 
|-
 
|-
 
| linear
 
| linear
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|  
 
|  
 
{| class="collapsible collapsed" style="width:150px"
 
{| class="collapsible collapsed" style="width:150px"
−
! Polyether
+
! Polyether (LE)
 
|-
 
|-
 
| nigericin
 
| nigericin
 
|-
 
|-
 
| monensin
 
| monensin
−
|}
 
−
| Acetogenins
 
−
|
 
−
{| class="collapsible collapsed" style="width:150px"
 
−
! Cyclic imines
 
 
|-
 
|-
−
| Spirolide
+
| okadaic acid
 
|-
 
|-
−
| Pinnatoxin
+
| ciguatoxin, brevetoxin
 +
|-
 +
| halichondrin
 +
|-
 +
| zaragozic acid
 
|}
 
|}
 +
| Acetogenins (LA)
 +
|
 
|-  
 
|-  
−
!colspan="4"| Aromatic and Related
+
!colspan="4"| Aromatic and Diels-Alder Related (most often by iterative type II)
 
|-
 
|-
 
|  
 
|  
 
{| class="collapsible collapsed" style="width:150px"
 
{| class="collapsible collapsed" style="width:150px"
−
! with Benzene
+
! Monocyclic (A1)
 
|-
 
|-
−
| salicylic acid
+
| Salicylic acid
 
|-
 
|-
 
| orsellinic acid
 
| orsellinic acid
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|  
 
|  
 
{| class="collapsible collapsed"  
 
{| class="collapsible collapsed"  
−
! with Naphthalene
+
! Bicyclic (A2)
 
|-
 
|-
 
| lovastatin
 
| lovastatin
 
|-
 
|-
−
| aflatoxins
+
| aflatoxins<ref></ref>
 
|}
 
|}
 
|  
 
|  
 
{| class="collapsible collapsed"  
 
{| class="collapsible collapsed"  
−
! with Anthracene
+
! Tricyclic (A3)
 
|-
 
|-
 
| emodin
 
| emodin
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|
 
|
 
{| class="collapsible collapsed" style="width:150px"
 
{| class="collapsible collapsed" style="width:150px"
−
! Tetracycline
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! Tetracyclic (A4)
 
|-
 
|-
 
| Linear type
 
| Linear type
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!colspan="4"| Macrolides (most often by non-iterative type I)
 
!colspan="4"| Macrolides (most often by non-iterative type I)
 
|-
 
|-
−
|style="width:150px"| Polyene Type
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|style="width:150px"|
−
* Manumycin
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{| class="collapsible collapsed" style="width:150px"
−
* Nystatin
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! Polyene (MN)
−
* Amphotericin
+
|-
−
|style="width:150px"| Macrolides
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| Manumycin
−
* Ansamycin
+
|-
−
* Avermectin (16-membered), Milbemycin (20-membered)
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| Nystatin
−
* Bafilomycin (16-membered)
+
|-
−
* Bryostatin (26-membered. lacks AT domain as in mupirocin, leinamycin<ref>Nguyen T, Ishida K, Jenke-Kodama H, Dittmann E, Gurgui C, Hochmuth T, Taudien S, Platzer M, Hertweck C, Piel J (2008) "Exploiting the mosaic structure of trans-acyltransferase polyketide synthases for natural product discovery and pathway dissection" ''Nat Biotechnol'' 26:225 - 233 PMID 18223641</ref>)
+
| Amphotericin
−
* Colletodiol (14-membered)
+
|}
−
* Cytovaricin
+
|style="width:150px"|  
−
* Erythromycin (14-membered) 6-deoxy sugars (L-cladinose and D-desosamine) are attached.
+
{| class="collapsible collapsed" style="width:150px"
−
* Fluvirucin (14-membered)
+
! Cyclic Imines (MI)
−
* Myxovirescin (28-membered http://www.indiana.edu/~drwchem/pdfs/50.pdf)
+
|-
−
* Nonactin, Nactin
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| Spirolide
−
* Natamycin (26-membered =Pimaricin)
+
|-
−
* Oligomycin (16-membered)
+
| Pinnatoxin
−
* Tacrolimus (23-membered =FK-506 or Fujimycin)
+
|}
−
* Tylosin (16-memberd)
+
|style="width:150px"|
 +
{| class="collapsible collapsed" style="width:150px"
 +
! Ansamacrolide (MA)
 +
|-
 +
| Rifamycin
 +
|-
 +
| Ansamycin
 +
|}
 +
|style="width:150px"|
 +
{| class="collapsible collapsed" style="width:150px"
 +
! Polyether (ME)
 +
|-
 +
| Nonactin, Nactin
 +
|}
 +
|-
 +
|style="width:150px"|
 +
{| class="collapsible collapsed" style="width:150px"
 +
! 12-membered (M2)
 +
|-
 
|
 
|
 +
|}
 +
|style="width:150px"|
 +
{| class="collapsible collapsed" style="width:150px"
 +
! 14-membered (M4)
 +
|-
 +
| Colletodiol
 +
|-
 +
| Erythromycin<ref>6-deoxy sugars (L-cladinose and D-desosamine) are attached.</ref>
 +
|-
 +
| Fluvirucin
 +
|-
 +
| Zearalenone
 +
|}
 +
|style="width:150px"|
 +
{| class="collapsible collapsed" style="width:150px"
 +
! 16-membered (M6)
 +
|-
 +
| Avermectin
 +
|-
 +
| Bafilomycin
 +
|-
 +
| Oligomycin
 +
|-
 +
| Tylosin
 +
|}
 +
|style="width:150px"|
 +
{| class="collapsible collapsed" style="width:150px"
 +
! More (MM)
 +
|-
 +
| Bryostatin (26)<ref>It lacks AT domain as in mupirocin, leinamycin<ref>Nguyen T, Ishida K, Jenke-Kodama H, Dittmann E, Gurgui C, Hochmuth T, Taudien S, Platzer M, Hertweck C, Piel J (2008) "Exploiting the mosaic structure of trans-acyltransferase polyketide synthases for natural product discovery and pathway dissection" ''Nat Biotechnol'' 26:225 - 233 PMID 18223641</ref>
 +
|-
 +
| Milbemycin (20)
 +
|-
 +
| Myxovirescin (28)<ref>http://www.indiana.edu/~drwchem/pdfs/50.pdf</ref>
 +
|-
 +
| Natamycin (26)<ref>=Pimaricin</ref>
 +
|-
 +
| Tacrolimus (23)
 +
|}
 
|}
 
|}
  

Revision as of 00:28, 18 December 2010

Polyketide (ポリケチド)

Contents

Class Overview

Polyketides are synthesized through the polymerization of acetyl units (β-ketomethylene) as in fatty acid biosynthesis. Typical starter units are short-chain fatty acids (e.g. acetyl-CoA or propionyl-CoA), on to which extender units (e.g. malonyl-CoA or methylmalonyl-CoA) are repeatedly polymerized. The key reactions for the chain extension are:

  • Claisen condensation by β-ketoacyl synthase (KS)
  • an acyltransferase (AT), and
  • an acyl carrier protein (ACP).
After elongation, β-ketone is reduced. In fatty acid biosynthesis, the chain is fully reduced by the following three steps:
  • 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).
In polyketide synthase, the reduction is patial. Finally, the chain is terminated by a thioesterase (TE) activity and allows Claisen cyclization (CYC).

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


Linear Chain and Related ()
Acetogenins (LA)
Aromatic and Diels-Alder Related (most often by iterative type II)
Macrolides (most often by non-iterative type I)

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)



Cite error: <ref> tags exist, but no <references/> tag was found

Subcategories

This category has only the following subcategory.

P

  • [×] PKS‎ (empty)
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