Type II Polyketide Synthases: Gaining a Deeper Insight into Enzymatic Teamwork

Leibniz Institute for Natural Product Research and Infection Biology, HKI, Beutenbergstrasse 11a, 07745 Jena, Germany.
Natural Product Reports (Impact Factor: 10.11). 03/2007; 24(1):162-90. DOI: 10.1039/b507395m
Source: PubMed


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

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Available from: Andriy Luzhetskyy,
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    • "Notably, a few anthracyclines and tetracyclines have emerged as clinical drugs for decades, such as doxorubicin (antineoplastic) and tetracycline (antibiotic). Furthermore, many of these compounds are promising drug candidates (Hertweck et al., 2007). Therefore, sponge-associated actinomycetes may provide chemical defense for their hosts by producing aromatic polyketides. "
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    ABSTRACT: Marine sponges often harbor dense and diverse microbial communities including actinobacteria. To date no comprehensive investigation has been performed on the culturable diversity of the actinomycetes associated with South China Sea sponges. Structurally novel aromatic polyketides were recently discovered from marine sponge-derived Streptomyces and Saccharopolyspora strains, suggesting that sponge-associated actinomycetes can serve as a new source of aromatic polyketides. In this study, a total of 77 actinomycete strains were isolated from 15 South China Sea sponge species. Phylogenetic characterization of the isolates based on 16S rRNA gene sequencing supported their assignment to 12 families and 20 genera, among which three rare genera (Marihabitans, Polymorphospora, and Streptomonospora) were isolated from marine sponges for the first time. Subsequently, β-ketoacyl synthase (KSα) gene was used as marker for evaluating the potential of the actinomycete strains to produce aromatic polyketides. As a result, KSα gene was detected in 35 isolates related to seven genera (Kocuria, Micromonospora, Nocardia, Nocardiopsis, Saccharopolyspora, Salinispora, and Streptomyces). Finally, 10 strains were selected for small-scale fermentation, and one angucycline compound was detected from the culture extract of Streptomyces anulatus strain S71. This study advanced our knowledge of the sponge-associated actinomycetes regarding their diversity and potential in producing aromatic polyketides.
    Frontiers in Microbiology 10/2015; 6. DOI:10.3389/fmicb.2015.01048 · 3.99 Impact Factor
    • "The biosynthesis of angucyclines is initiated by the iterative action of a minimal polyketide synthase (PKS) complex consisting of a β-ketoacyl synthase/chain length factor heterodimer (KS α /KS β or KS α /CLF) and an acyl carrier protein (ACP), which is responsible for the production of decaketides through repeated Claisen condensations of malonyl-CoA units (Hertweck et al., 2007; Kharel et al., 2012a). The highly reactive polyketide chain remains tethered to the ACP during these early stages, and the sequence of events that lead to the formation of the first stable intermediate of many of the pathways, prejadomycin (4), have been elucidated during the past decade (Kharel and Rohr, 2012; Metsä-Ketelä et al., 2003). "
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    ABSTRACT: Angucyclines are tetracyclic polyketides produced by Streptomyces bacteria that exhibit notable biological activities. The great diversity of angucyclinones is generated in tailoring reactions, which modify the common benz[a]anthraquinone carbon skeleton. In particular, the opposite stereochemistry of landomycins and urdamycins/gaudimycins at C-6 is generated by the short-chain alcohol dehydrogenases/reductases LanV and UrdMred/CabV, respectively. Here we present crystal structures of LanV and UrdMred in complex with NADP(+) and the product analog rabelomycin, which enabled us to identify four regions associated with the functional differentiation. The structural analysis was confirmed in chimeragenesis experiments focusing on these regions adjacent to the active site cavity, which led to reversal of the activities of LanV and CabV. The results surprisingly indicated that the conformation of the substrate and the stereochemical outcome of 6-ketoreduction appear to be intimately linked.
    Chemistry & Biology 10/2014; 21(10). DOI:10.1016/j.chembiol.2014.07.017 · 6.65 Impact Factor
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    • "The construction of its precursor, 6-deoxyerythronolide B (6-deB) is controlled by a large modular protein known as 6-deB synthase (DEBS) (Fig. 4A). Type II PKSs consist of several monofunctional enzymes acting iteratively, resulting in the production of polyphenols or other aromatic polyketides (Hertweck et al., 2007). An example of this type is the anti-tumour antibiotic doxorubicin, which is produced by the actinomycete Streptomyces peucetius ATCC29050 (Fig. 4B) (Grimm et al., 1994). "
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    ABSTRACT: Natural product drug discovery has regained interest due to low production costs, structural diversity, and multiple uses of active compounds to treat various diseases. Attention has been directed towards medicinal plants as these plants have been traditionally used for generations to treat symptoms of numerous diseases. It is established that plants harbour microorganisms, collectively known as endophytes. Exploring the as-yet untapped natural products from the endophytes increases the chances of finding novel compounds. The concept of natural products targeting microbial pathogens has been applied to isolate novel antimycobacterial compounds, and the rapid development of drug-resistant Mycobacterium tuberculosis has significantly increased the need for new treatments against this pathogen. It remains important to continuously screen for novel compounds from natural sources, particularly from rarely encountered microorganisms, such as the endophytes. This review focuses on bioprospecting for polyketides and small peptides exhibiting antituberculosis activity, although current treatments against tuberculosis are described. It is established that natural products from these structure classes are often biosynthesised by microorganisms. Therefore it is hypothesised that some bioactive polyketides and peptides originally isolated from plants are in fact produced by their endophytes. This is of interest for further endophyte natural product investigations (Figure 1).
    Microbiological Research 07/2014; 169(7). DOI:10.1016/j.micres.2013.12.009 · 2.56 Impact Factor
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