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Natural Product Reports Jan 2009This review covers the biosynthesis of extender units that are utilized for the assembly of polyketides by polyketide synthases. The metabolic origins of each of the... (Review)
Review
This review covers the biosynthesis of extender units that are utilized for the assembly of polyketides by polyketide synthases. The metabolic origins of each of the currently known polyketide synthase extender units are covered.
Topics: Biological Products; Molecular Structure; Polyketide Synthases
PubMed: 19374124
DOI: 10.1039/b801658p -
Angewandte Chemie (International Ed. in... Jun 2022(Pre-)anthraquinones are widely distributed natural compounds and occur in plants, fungi, microorganisms, and animals, with atrochrysone (1) as the key biosynthetic...
(Pre-)anthraquinones are widely distributed natural compounds and occur in plants, fungi, microorganisms, and animals, with atrochrysone (1) as the key biosynthetic precursor. Chemical analyses established mushrooms of the genus Cortinarius-the webcaps-as producers of atrochrysone-derived octaketide pigments. However, more recent genomic data did not provide any evidence for known atrochrysone carboxylic acid (4) synthases nor any other polyketide synthase (PKS) producing oligocyclic metabolites. Here, we describe an unprecedented class of non-reducing (NR-)PKS. In vitro assays with recombinant enzyme in combination with in vivo product formation in the heterologous host Aspergillus niger established CoPKS1 and CoPKS4 of C. odorifer as members of a new class of atrochrysone carboxylic acid synthases. CoPKS4 catalyzed both hepta- and octaketide synthesis and yielded 6-hydroxymusizin (6), along with 4. These first mushroom PKSs for oligocyclic products illustrate how the biosynthesis of bioactive natural metabolites evolved independently in various groups of life.
Topics: Agaricales; Anthraquinones; Polyketide Synthases; Polyketides
PubMed: 35218274
DOI: 10.1002/anie.202116142 -
BMC Plant Biology Apr 2022Sesame is a great reservoir of bioactive constituents and unique antioxidant components. It is widely used for its nutritional and medicinal value. The expanding demand...
BACKGROUND
Sesame is a great reservoir of bioactive constituents and unique antioxidant components. It is widely used for its nutritional and medicinal value. The expanding demand for sesame seeds is putting pressure on sesame breeders to develop high-yielding varieties. A hybrid breeding strategy based on male sterility is one of the most effective ways to increase the crop yield. To date, little is known about the genes and mechanism underlying sesame male fertility. Therefore, studies are being conducted to identify and functionally characterize key candidate genes involved in sesame pollen development. Polyketide synthases (PKSs) are critical enzymes involved in the biosynthesis of sporopollenin, the primary component of pollen exine. Their in planta functions are being investigated for applications in crop breeding.
RESULTS
In this study, we cloned the sesame POLYKETIDE SYNTHASE A (SiPKSA) and examined its function in male sterility. SiPKSA was specifically expressed in sesame flower buds, and its expression was significantly higher in sterile sesame anthers than in fertile anthers during the tetrad and microspore development stages. Furthermore, overexpression of SiPKSA in Arabidopsis caused male sterility in transgenic plants. Ultrastructural observation showed that the pollen grains of SiPKSA-overexpressing plants contained few cytoplasmic inclusions and exhibited an abnormal pollen wall structure, with a thicker exine layer compared to the wild type. In agreement with this, the expression of a set of sporopollenin biosynthesis-related genes and the contents of their fatty acids and phenolics were significantly altered in anthers of SiPKSA-overexpressing plants compared with wild type during anther development.
CONCLUSION
These findings highlighted that overexpression of SiPKSA in Arabidopsis might cause male sterility through defective pollen wall formation. Moreover, they suggested that SiPKSA modulates vibrant pollen development via sporopollenin biosynthesis, and a defect in its regulation may induce male sterility. Therefore, genetic manipulation of SiPKSA might promote hybrid breeding in sesame and other crop species.
Topics: Arabidopsis; Arabidopsis Proteins; Plant Breeding; Pollen; Polyketide Synthases; Sesamum
PubMed: 35366814
DOI: 10.1186/s12870-022-03551-7 -
MSystems Jun 2023Microbial polyketide synthase (PKS) genes encode the biosynthesis of many biomedically or otherwise commercially important natural products. Despite extensive discovery...
Microbial polyketide synthase (PKS) genes encode the biosynthesis of many biomedically or otherwise commercially important natural products. Despite extensive discovery efforts, metagenomic analyses suggest that only a small fraction of nature's polyketide biosynthetic potential has been realized. Much of this potential originates from type I PKSs (T1PKSs), which can be further delineated based on their domain organization and the structural features of the compounds they encode. Notably, phylogenetic relationships among ketosynthase (KS) domains provide an effective method to classify the larger and more complex T1PKS genes in which they occur. Increased access to large metagenomic data sets from diverse habitats provides opportunities to assess T1PKS biosynthetic diversity and distributions through their smaller and more tractable KS domain sequences. Here, we used the web tool NaPDoS2 to detect and classify over 35,000 type I KS domains from 137 metagenomic data sets reported from eight diverse, globally distributed biomes. We found biome-specific separation with soils enriched in KSs from modular -acetyltransferase (AT) and hybrid -AT KSs relative to other biomes and marine sediments enriched in KSs associated with polyunsaturated fatty acid and enediyne biosynthesis. We linked the phylum Actinobacteria to soil-derived enediyne and -AT KSs while marine-derived KSs associated with enediyne and monomodular PKSs were linked to phyla from which the compounds produced by these biosynthetic enzymes have not been reported. These KSs were phylogenetically distinct from those associated with experimentally characterized PKSs suggesting they may be associated with novel structures or enzyme functions. Finally, we employed our metagenome-extracted KS domains to evaluate the PCR primers commonly used to amplify type I KSs and identified modifications that could increase the KS sequence diversity recovered from amplicon libraries. IMPORTANCE Polyketides are a crucial source of medicines, agrichemicals, and other commercial products. Advances in our understanding of polyketide biosynthesis, coupled with the increased availability of metagenomic sequence data, provide new opportunities to assess polyketide biosynthetic potential across biomes. Here, we used the web tool NaPDoS2 to assess type I polyketide synthase (PKS) diversity and distributions by detecting and classifying ketosynthase (KS) domains across 137 metagenomes. We show that biomes are differentially enriched in type I KS domains, providing a roadmap for future biodiscovery strategies. Furthermore, KS phylogenies reveal biome-specific clades that do not include biochemically characterized PKSs, highlighting the biosynthetic potential of poorly explored environments. The large metagenome-derived KS data set allowed us to identify regions of commonly used type I KS PCR primers that could be modified to capture a larger extent of environmental KS diversity. These results facilitate both the search for novel polyketides and our understanding of the biogeographical distribution of PKSs across Earth's major biomes.
Topics: Polyketide Synthases; Metagenome; Phylogeny; Polyketides; Enediynes
PubMed: 37272717
DOI: 10.1128/msystems.00012-23 -
Zebrafish Aug 2019Otoliths (ear stones) are biomineralized complexes essential for the balancing and hearing function of the inner ears in fish. Their formation is controlled by a...
Otoliths (ear stones) are biomineralized complexes essential for the balancing and hearing function of the inner ears in fish. Their formation is controlled by a genetically programmed biological process that is yet to be defined. We have isolated and characterized a spontaneous genetic mutant zebrafish with a complete absence of otoliths, named (). mutants are unable to develop otoliths during embryonic stages and fail to respond to acoustic stimuli, indicating an inner ear defect. We identified a deleterious mutation (G239R) that altered a highly conserved amino acid residue in the zebrafish ortholog of type I polyketide synthase () to underlie these phenotypes and showed that expression of the polyketide synthase gene of Japanese medaka fish could rescue the otolith deficiency in mutant zebrafish. Our finding highlights a critical and conserved role of type I polyketide synthase in the initiation of otolith formation. Given the functional homology between otoliths in teleost fish and otoconia in mammals and humans, mutants provide a new animal model for the study of human otoconia-related diseases.
Topics: Animals; Embryonic Development; Organogenesis; Oryzias; Otolithic Membrane; Polyketide Synthases; Zebrafish; Zebrafish Proteins
PubMed: 31188077
DOI: 10.1089/zeb.2019.1734 -
Proceedings of the National Academy of... Sep 2023Animal cytoplasmic fatty acid synthase (FAS) represents a unique family of enzymes that are classically thought to be most closely related to fungal polyketide synthase...
Animal cytoplasmic fatty acid synthase (FAS) represents a unique family of enzymes that are classically thought to be most closely related to fungal polyketide synthase (PKS). Recently, a widespread family of animal lipid metabolic enzymes has been described that bridges the gap between these two ubiquitous and important enzyme classes: the animal FAS-like PKSs (AFPKs). Although very similar in sequence to FAS enzymes that produce saturated lipids widely found in animals, AFPKs instead produce structurally diverse compounds that resemble bioactive polyketides. Little is known about the factors that bridge lipid and polyketide synthesis in the animals. Here, we describe the function of EcPKS2 from , which synthesizes a complex polypropionate natural product found in this mollusc. EcPKS2 starter unit promiscuity potentially explains the high diversity of polyketides found in and among molluscan species. Biochemical comparison of EcPKS2 with the previously described EcPKS1 reveals molecular principles governing substrate selectivity that should apply to related enzymes encoded within the genomes of photosynthetic gastropods. Hybridization experiments combining EcPKS1 and EcPKS2 demonstrate the interactions between the ketoreductase and ketosynthase domains in governing the product outcomes. Overall, these findings enable an understanding of the molecular principles of structural diversity underlying the many molluscan polyketides likely produced by the diverse AFPK enzyme family.
Topics: Animals; Polyketide Synthases; Fatty Acid Synthases; Biological Products; Gastropoda; Polyketides; Lipids
PubMed: 37695909
DOI: 10.1073/pnas.2305575120 -
Current Opinion in Chemical Biology Apr 2009Modularity is a highly sought after feature in engineering design. A modular catalyst is a multi-component system whose parts can be predictably interchanged for... (Review)
Review
Modularity is a highly sought after feature in engineering design. A modular catalyst is a multi-component system whose parts can be predictably interchanged for functional flexibility and variety. Nearly two decades after the discovery of the first modular polyketide synthase (PKS), we critically assess PKS modularity in the face of a growing body of atomic structural and in vitro biochemical investigations. Both the architectural modularity and the functional modularity of this family of enzymatic assembly lines are reviewed, and the fundamental challenges that lie ahead for the rational exploitation of their full biosynthetic potential are discussed.
Topics: Biocatalysis; Biosynthetic Pathways; Polyketide Synthases
PubMed: 19217343
DOI: 10.1016/j.cbpa.2008.12.018 -
Proceedings. Biological Sciences Aug 2022Organisms living on the seafloor are subject to encrustations by a wide variety of animals, plants and microbes. Sea urchins, however, thwart this covering. Despite...
Organisms living on the seafloor are subject to encrustations by a wide variety of animals, plants and microbes. Sea urchins, however, thwart this covering. Despite having a sophisticated immune system, there is no clear molecular mechanism that allows sea urchins to remain free of epibiotic microorganisms. Here, we test the hypothesis that pigmentation biosynthesis in sea urchin spines influences their interactions with microbes using CRISPR/Cas9. We report three primary findings. First, the microbiome of sea urchin spines is species-specific and much of this community is lost in captivity. Second, different colour morphs associate with bacterial communities that are similar in taxonomic composition, diversity and evenness. Lastly, loss of the pigmentation biosynthesis genes polyketide synthase and flavin-dependent monooxygenase induces a shift in which bacterial taxa colonize sea urchin spines. Therefore, our results are consistent with the hypothesis that host pigmentation biosynthesis can, but may not always, influence the microbiome in sea urchin spines.
Topics: Animals; Bacteria; Microbiota; Pigmentation; Polyketide Synthases; Sea Urchins
PubMed: 35975446
DOI: 10.1098/rspb.2022.1088 -
Genome Biology and Evolution May 2020Major phenotypic innovations in social amoeba evolution occurred at the transition between the Polysphondylia and group 4 Dictyostelia, which comprise the model organism...
Major phenotypic innovations in social amoeba evolution occurred at the transition between the Polysphondylia and group 4 Dictyostelia, which comprise the model organism Dictyostelium discoideum, such as the formation of a new structure, the basal disk. Basal disk differentiation and robust stalk formation require the morphogen DIF-1, synthesized by the polyketide synthase StlB, the des-methyl-DIF-1 methyltransferase DmtA, and the chlorinase ChlA, which are conserved throughout Dictyostelia. To understand how the basal disk and other innovations evolved in group 4, we sequenced and annotated the Polysphondylium violaceum (Pvio) genome, performed cell type-specific transcriptomics to identify cell-type marker genes, and developed transformation and gene knock-out procedures for Pvio. We used the novel methods to delete the Pvio stlB gene. The Pvio stlB- mutants formed misshapen curly sorogens with thick and irregular stalks. As fruiting body formation continued, the upper stalks became more regular, but structures contained 40% less spores. The stlB- sorogens overexpressed a stalk gene and underexpressed a (pre)spore gene. Normal fruiting body formation and sporulation were restored in Pvio stlB- by including DIF-1 in the supporting agar. These data indicate that, although conserved, stlB and its product(s) acquired both a novel role in the group 4 Dictyostelia and a role opposite to that in its sister group.
Topics: Genome, Protozoan; Myxomycetes; Polyketide Synthases; Protozoan Proteins
PubMed: 32386295
DOI: 10.1093/gbe/evaa079 -
Proteins Sep 2021The loops of modular polyketide synthases (PKSs) serve diverse functions but are largely uncharacterized. They frequently contain amino acid repeats resulting from...
The loops of modular polyketide synthases (PKSs) serve diverse functions but are largely uncharacterized. They frequently contain amino acid repeats resulting from genetic events such as slipped-strand mispairing. Determining the tolerance of loops to amino acid changes would aid in understanding and engineering these multidomain molecule factories. Here, tandem repeats in the DNA encoding 949 modules within 129 cis-acyltransferase PKSs were cataloged, and the locations of the corresponding amino acids within the module were identified. The most frequently inserted interdomain loop corresponds with the updated module boundary immediately downstream of the ketosynthase (KS), while the loops bordering the dehydratase are nearly intolerant to such insertions. From the 949 modules, no repetitive sequence loop insertions are located within ACP, and only 2 reside within KS, indicating the sensitivity of these domains to alteration.
Topics: Acyl Carrier Protein; Acyltransferases; Amino Acid Sequence; Bacteria; Bacterial Proteins; Binding Sites; Cloning, Molecular; Crystallography, X-Ray; Escherichia coli; Gene Expression; Genetic Vectors; Kinetics; Models, Molecular; Polyketide Synthases; Polyketides; Protein Binding; Protein Conformation, alpha-Helical; Protein Conformation, beta-Strand; Protein Interaction Domains and Motifs; Recombinant Proteins; Sequence Alignment; Sequence Homology, Amino Acid; Substrate Specificity; Thermodynamics
PubMed: 33843112
DOI: 10.1002/prot.26083