Type II polyketide synthases: gaining a deeper insight into enzymatic teamwork

Hertweck, Christian; Luzhetskyy, Andriy; Rebets, Yuri; Bechthold, Andreas

doi:10.1039/b507395m

Cited by 490 publications

(499 citation statements)

References 269 publications

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“…The biosynthesis of aromatic polyketides requires the coordinated action of several enzymes, a type II polyketide synthase (PKS) that elongates the polyketide chain from malonyl-CoA units, an ACP molecule that carries the growing polyketide and additional PKS components such as ketoreductases and polyketide cyclases (for recent reviews see [1][2][3][4]). A particular striking example of the interplay between polyketide biosynthetic enzymes is the biosynthesis of resistomycin, an unusual pentacyclic aromatic polyketide produced by Streptomyces resistomycificus [5].…”

Section: Introductionmentioning

confidence: 99%

The polyketide cyclase RemF from Streptomyces resistomycificus contains an unusual octahedral zinc binding site

2009

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a b s t r a c tRemF is a polyketide cyclase involved in the biosynthesis of the aromatic pentacyclic metabolite resistomycin in Streptomyces resistomycificus. The enzyme is a member of a structurally hitherto uncharacterized class of polyketide cyclases. The crystal structure of RemF was determined by SAD and refined to 1.2 Å resolution. The enzyme subunit shows a b-sandwich structure with a topology characteristic for the cupin fold. RemF contains a metal binding site located at the bottom of the predominantly hydrophobic active site cavity. A zinc ion is coordinated to four histidine side chains, and two water molecules in octahedral ligand sphere geometry, highly unusual for zinc binding sites in proteins.

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Section: Introductionmentioning

confidence: 99%

The polyketide cyclase RemF from Streptomyces resistomycificus contains an unusual octahedral zinc binding site

2009

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“…4,[15][16][17] Among the homologous enzymes, the R1128 biosynthetic enzymes ZhuH (KSIII), ZhuG (ACP) and ZhuC (AT) were well studied. 15 ZhuH catalyzes the Claisen-type condensation between malonylated ZhuG and the acyl CoAs to afford the corresponding diketide intermediates on ZhuG.…”

Section: Conserved Polyketide Biosynthetic Genesmentioning

confidence: 99%

“…4 All are formed by type II polyketide synthases (PKSs), which are comprised of two ketosynthases (KSa and KSb) and an acyl carrier protein (ACP). The set of KSa/KSb/ACP, designated as a minimal PKS, catalyzes the polyketide chain growth.…”

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confidence: 99%

Cloning of the biosynthetic gene cluster for naphthoxanthene antibiotic FD-594 from Streptomyces sp. TA-0256

et al. 2010

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FD-594 is an unique pyrano [4¢,3¢:6,7]naphtho [1,2-b]xanthene polyketide with a trisaccharide of 2,6-dideoxysugars. In this study, we cloned the FD-594 biosynthetic gene cluster from the producer strain Streptomyces sp. TA-0256 to investigate its biosynthesis. The identified pnx gene cluster was 38 143 bp, consisting of 40 open reading frames, including a minimal PKS gene, TDP-olivose biosynthetic genes, two glycosyltransferase genes, two methyltransferase genes and many oxygenase/reductase genes. Most of these enzymes coded in the pnx cluster were reasonably assigned to a plausible biosynthetic pathway for FD-594, in which an unique ring opening process via Baeyer-Villiger-type oxidation catalyzed by a putative flavin adenine dinucleotide (FAD)-dependent monooxygenase, is speculated to lead to the unique xanthene structure. To clarify the involvement of pnx genes in the FD-594 biosynthesis, a glycosyltransferase, PnxGT2, and a methyltransferase, PnxMT2, were characterized enzymatically with the recombinant proteins expressed in Escherichia coli. As a result, PnxGT2 catalyzed the triple olivose transfers to the FD-594 aglycon with TDP-olivose as the glycosyl donor to afford triolivoside. Surprisingly, in the PnxGT2 enzymatic reaction, tetraolivoside and pentaolivoside were significantly detected along with the expected triolivoside. To our knowledge, PnxGT2 is the first contiguous oligosaccharide-forming glycosyltransferase in secondary metabolism. Furthermore, addition of PnxMT2 and S-adenosyl-L-methionine into the PnxGT2 reaction mixture afforded natural FD-594 to confirm that the PnxGT2 reaction product was the expected regiospecifically glycosylated compound. Consequently, the identified pnx gene cluster appears to be involved in FD-594 biosynthesis.

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“…[1][2][3] Some of them are produced by polyketide synthases (PKSs), and have been linked to their biosynthetic genes. However, there are a large number of PKS genes with products that have not been identified in several fungal genome sequences, indicating that numerous cryptic biosynthetic pathways of natural products remain to be discovered.…”

Section: Introductionmentioning

confidence: 99%

Induced biosyntheses of a novel butyrophenone and two aromatic polyketides in the plant pathogen Stagonospora nodorum

Yang

Awakawa

Wakimoto

et al. 2013

Nat. Prod. Bioprospect.

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Fungal aromatic compounds comprise an important and structurally diverse group of secondary metabolites. Several genome sequencing projects revealed many putative biosynthetic gene clusters of fungal aromatic compounds, but many of these genes seem to be silent under typical laboratory culture conditions. To gain access to this untapped reservoir of natural products, we utilized chemical epigenetic modifiers to induce the expression of dormant biosynthetic genes. As a result, the concomitant supplementation of the histone deacetylase inhibitors suberoylanilide hydroxamic acid (500 M) and nicotinamide (50 M) to the culture medium of a fungal pathogen, Stagonospora nodorum, resulted in the isolation of three aromatic compounds (1-3), including a novel natural butyrophenone, (+)-4'-methoxy-(2S)-methylbutyrophenone (1), and two known polyketides, alternariol (2) and (-)-(3R)-mellein methyl ether (3).

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Type II polyketide synthases: gaining a deeper insight into enzymatic teamwork

Abstract: This review covers advances in understanding of the biosynthesis of polyketides produced by type II PKS systems at the genetic, biochemical and structural levels.

Cited by 490 publications

References 269 publications

The polyketide cyclase RemF from Streptomyces resistomycificus contains an unusual octahedral zinc binding site

The polyketide cyclase RemF from Streptomyces resistomycificus contains an unusual octahedral zinc binding site

Cloning of the biosynthetic gene cluster for naphthoxanthene antibiotic FD-594 from Streptomyces sp. TA-0256

Induced biosyntheses of a novel butyrophenone and two aromatic polyketides in the plant pathogen Stagonospora nodorum

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