Polyketide (ポリケチド)
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 (L)
|
|
Polyether (LE)
|
nigericin
|
monensin
|
okadaic acid
|
ciguatoxin, brevetoxin
|
halichondrin
|
zaragozic acid
|
|
Acetogenins (LA)
|
|
Aromatic and Diels-Alder Related (most often by iterative type II)
|
Monocyclic (A1)
|
Salicylic acid
|
orsellinic acid
|
benzophenone
|
altenariol
|
|
Bicyclic (A2)
|
lovastatin
|
aflatoxinsCite error: Invalid <ref> tag;
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|
|
Tricyclic (A3)
|
emodin
|
sennoside
|
hypericin
|
|
Tetracyclic (A4)
|
Linear type
|
Angucycline
|
|
|
Macrolides (most often by non-iterative type I)
|
|
14-membered (M4)
|
Colletodiol
|
Erythromycin[1]
|
Fluvirucin
|
Zearalenone
|
|
16-membered (M6)
|
Avermectin
|
Bafilomycin
|
Oligomycin
|
Tylosin
|
|
Polyene (MN)
|
Manumycin
|
Nystatin
|
Amphotericin
|
|
Polyether (ME)
|
Nonactin, Nactin
|
|
Cyclic Imines (MI)
|
Spirolide
|
Pinnatoxin
|
|
Ansamacrolide (MA)
|
Rifamycin
|
Ansamycin
|
|
Others (MO)
|
Bryostatin (26)Cite error: Closing </ref> missing for <ref> tag
|
Milbemycin (20)
|
Myxovirescin (28)[2]
|
Natamycin (26)[3]
|
Tacrolimus (23)
|
|
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
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