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: 10.72). 03/2007; 24(1):162-90. DOI: 10.1039/b507395m
Source: PubMed

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.

Download full-text


Available from: Andriy Luzhetskyy, Jul 31, 2015
1 Follower
    • "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). "
    [Show abstract] [Hide abstract]
    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 · 6.59 Impact Factor
  • Source
    • "In analogy with the evolutionarily related fatty acid synthases, they are classified into Type I and Type II PKSs (Hopwood and Sherman, 1990; Smith and Tsai, 2007). The latter sub-class of PKSs, which resemble bacterial and plant fatty acid synthases, play a defining role in the biosynthesis of many polycyclic aromatic antibiotics produced by the actinomycetes (Das and Khosla, 2009; Hertweck et al., 2007). They invariably harbor a minimal PKS module comprised of a ketosynthase (KS), a chain length factor (CLF), an acyl carrier protein (ACP), and a malonyl-CoA:ACP transacylase (MAT, usually from the housekeeping fatty acid synthase in the bacterium). "
    [Show abstract] [Hide abstract]
    ABSTRACT: The pentadecaketide fredericamycin has the longest carbon chain backbone among polycyclic aromatic polyketide antibiotics whose biosynthetic genes have been sequenced. This backbone is synthesized by the bimodular fdm polyketide synthase (PKS). Here, we demonstrate that the bimodular fdm PKS as well as its elongation module alone synthesize undecaketides and dodecaketides. Thus, unlike other homologs, the fdm ketosynthase-chain length factor (KS-CLF) heterodimer does not exclusively control the backbone length of its natural product. Using sequence- and structure-based approaches, 48 CLF multiple mutants were engineered and analyzed. Unexpectedly, the I134F mutant was unable to turn over but could initiate and partially elongate the polyketide chain. This unprecedented mutant suggests that the KS-CLF heterodimer harbors an as yet uncharacterized chain termination mechanism. Together, our findings reveal fundamental mechanistic differences between the fdm PKS and its well-studied homologs.
    Chemistry & biology 08/2011; 18(8):1021-31. DOI:10.1016/j.chembiol.2011.07.015 · 6.59 Impact Factor
  • Source
    • "Polyketide biosynthetic pathways are generally classified into three major groups: Type I, Type II, or Type III. Type II PKSs are composed of individual proteins that perform one enzymatic activity iteratively to catalyze the formation of aromatic polyketides such as the antibiotic actinorhodin (Hertweck et al., 2007). Type III PKSs participate in the assembly of small aromatic compounds and are found in plants and bacteria (Moore & Hopke, 2001). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Polyketides are structurally diverse secondary metabolites, many of which have antibiotic or anticancer activity. Type I modular polyketide synthase (PKS) genes are typically large and encode repeating enzymatic domains that elongate and modify the nascent polyketide chain. A fosmid metagenomic library constructed from an agricultural soil was arrayed and the macroarray was screened for the presence of conserved ketosynthase [β-ketoacyl synthase (KS)] domains, enzymatic domains present in PKSs. Thirty-four clones containing KS domains were identified by Southern hybridization. Many of the KS domains contained within metagenomic clones shared significant similarity to PKS or nonribosomal peptide synthesis genes from members of the Cyanobacteria or the Proteobacteria phyla. However, analysis of complete clone insert sequences indicated that the blast analysis for KS domains did not reflect the true phylogenetic origin of many of these metagenomic clones that had a %G+C content and significant sequence similarity to genes from members of the phylum Acidobacteria. This conclusion of an Acidobacteria origin for several clones was further supported by evidence that cultured soil Acidobacteria from different subdivisions have genetic loci closely related to PKS domains contained within metagenomic clones, suggesting that Acidobacteria may be a source of novel polyketides. This study also demonstrates the utility of combining data from culture-dependent and -independent investigations in expanding our collective knowledge of microbial genomic diversity.
    FEMS Microbiology Ecology 05/2011; 78(1):176-87. DOI:10.1111/j.1574-6941.2011.01122.x · 3.88 Impact Factor
Show more