polyketide synthases


Summary: Large enzyme complexes composed of a number of component enzymes that are found in STREPTOMYCES which biosynthesize MACROLIDES and other polyketides.

Top Publications

  1. Vagstad A, Bumpus S, Belecki K, Kelleher N, Townsend C. Interrogation of global active site occupancy of a fungal iterative polyketide synthase reveals strategies for maintaining biosynthetic fidelity. J Am Chem Soc. 2012;134:6865-77 pubmed publisher
    Nonreducing iterative polyketide synthases (NR-PKSs) are responsible for assembling the core of fungal aromatic natural products with diverse biological properties...
  2. Butchko R, Brown D, Busman M, Tudzynski B, Wiemann P. Lae1 regulates expression of multiple secondary metabolite gene clusters in Fusarium verticillioides. Fungal Genet Biol. 2012;49:602-12 pubmed publisher
    ..Fumonisin production is unchanged in the F. verticillioides lae1 mutant. Complementation of the F. verticillioides mutant resulted in increased fumonisin production. ..
  3. Abe I, Morita H. Structure and function of the chalcone synthase superfamily of plant type III polyketide synthases. Nat Prod Rep. 2010;27:809-38 pubmed publisher
  4. Medema M, Blin K, Cimermancic P, de Jager V, Zakrzewski P, Fischbach M, et al. antiSMASH: rapid identification, annotation and analysis of secondary metabolite biosynthesis gene clusters in bacterial and fungal genome sequences. Nucleic Acids Res. 2011;39:W339-46 pubmed publisher
    ..antiSMASH is available at http://antismash.secondarymetabolites.org. ..
  5. Kwan D, Leadlay P. Mutagenesis of a modular polyketide synthase enoylreductase domain reveals insights into catalysis and stereospecificity. ACS Chem Biol. 2010;5:829-38 pubmed publisher
    Modular type I polyketide synthases (PKSs) such as the 6-deoxyerythronolide B synthase (DEBS) or the rapamycin synthase (RAPS) biosynthesize their polyketide products in a fashion similar to fatty acid biosynthesis...
  6. Hochmuth T, Niederkrüger H, Gernert C, Siegl A, Taudien S, Platzer M, et al. Linking chemical and microbial diversity in marine sponges: possible role for poribacteria as producers of methyl-branched fatty acids. Chembiochem. 2010;11:2572-8 pubmed publisher
    ..Three components of this PKS were studied in vitro, providing initial insight into its biochemistry. ..
  7. Kapur S, Chen A, Cane D, Khosla C. Molecular recognition between ketosynthase and acyl carrier protein domains of the 6-deoxyerythronolide B synthase. Proc Natl Acad Sci U S A. 2010;107:22066-71 pubmed publisher
    ..a new principle in the modular control of polyketide antibiotic biosynthesis, they also provide a rationale for the mandatory homodimeric structure of polyketide synthases, in contrast to the monomeric nonribosomal peptide synthetases.
  8. Hansen D, Rath C, Eisman E, Narayan A, Kittendorf J, Mortison J, et al. Biocatalytic synthesis of pikromycin, methymycin, neomethymycin, novamethymycin, and ketomethymycin. J Am Chem Soc. 2013;135:11232-8 pubmed publisher
    A biocatalytic platform that employs the final two monomodular type I polyketide synthases of the pikromycin pathway in vitro followed by direct appendage of D-desosamine and final C-H oxidation(s) in vivo was developed and applied toward ..
  9. Gressler M, Zaehle C, Scherlach K, Hertweck C, Brock M. Multifactorial induction of an orphan PKS-NRPS gene cluster in Aspergillus terreus. Chem Biol. 2011;18:198-209 pubmed publisher
    ..Gene inactivation and stable isotope labeling experiments unveiled the molecular basis for flavipucine/fruit rot toxin biosynthesis. ..

More Information


  1. Sanchez J, Chiang Y, Szewczyk E, Davidson A, Ahuja M, Elizabeth Oakley C, et al. Molecular genetic analysis of the orsellinic acid/F9775 gene cluster of Aspergillus nidulans. Mol Biosyst. 2010;6:587-93 pubmed publisher
    ..Our deletions also yielded the bioactive metabolites gerfelin and diorcinol...
  2. Schmitt I, Lumbsch H. Ancient horizontal gene transfer from bacteria enhances biosynthetic capabilities of fungi. PLoS ONE. 2009;4:e4437 pubmed publisher
    ..To explain the amount of homology in some polyketide synthases in unrelated organisms such as bacteria and fungi, interkingdom horizontal gene transfer has been evoked as ..
  3. Masschelein J, Mattheus W, Gao L, Moons P, Van Houdt R, Uytterhoeven B, et al. A PKS/NRPS/FAS hybrid gene cluster from Serratia plymuthica RVH1 encoding the biosynthesis of three broad spectrum, zeamine-related antibiotics. PLoS ONE. 2013;8:e54143 pubmed publisher
    ..Most likely, the zeamine antibiotics are produced as prodrugs that undergo activation in which a nonribosomal peptide sequence is cleaved off. ..
  4. Dobritsa A, Lei Z, Nishikawa S, Urbanczyk Wochniak E, Huhman D, Preuss D, et al. LAP5 and LAP6 encode anther-specific proteins with similarity to chalcone synthase essential for pollen exine development in Arabidopsis. Plant Physiol. 2010;153:937-55 pubmed publisher
    ..Finally, the genetic interaction between LAP5 and an anther gene involved in fatty acid hydroxylation (CYP703A2) demonstrated that they act synergistically in exine production. ..
  5. Chiang Y, Oakley C, Ahuja M, Entwistle R, Schultz A, Chang S, et al. An efficient system for heterologous expression of secondary metabolite genes in Aspergillus nidulans. J Am Chem Soc. 2013;135:7720-31 pubmed publisher
    ..nidulans , and expressing them. We have validated this system by expressing nonreducing polyketide synthases of Aspergillus terreus and additional genes required for compound production and release...
  6. Kasahara K, Miyamoto T, Fujimoto T, Oguri H, Tokiwano T, Oikawa H, et al. Solanapyrone synthase, a possible Diels-Alderase and iterative type I polyketide synthase encoded in a biosynthetic gene cluster from Alternaria solani. Chembiochem. 2010;11:1245-52 pubmed publisher
  7. Valenzano C, Lawson R, Chen A, Khosla C, Cane D. The biochemical basis for stereochemical control in polyketide biosynthesis. J Am Chem Soc. 2009;131:18501-11 pubmed publisher
    ..centers, a series of incubations was carried out using reconstituted components from a variety of modular polyketide synthases. In all cases the stereochemistry of the product was directly correlated with the intrinsic ..
  8. Chiang Y, Oakley B, Keller N, Wang C. Unraveling polyketide synthesis in members of the genus Aspergillus. Appl Microbiol Biotechnol. 2010;86:1719-36 pubmed publisher
    ..to produce a wide range of secondary metabolites including polyketides that are generated by multi-domain polyketide synthases (PKSs)...
  9. Liu T, Chiang Y, Somoza A, Oakley B, Wang C. Engineering of an "unnatural" natural product by swapping polyketide synthase domains in Aspergillus nidulans. J Am Chem Soc. 2011;133:13314-6 pubmed publisher
    ..Structure elucidation allowed us to propose a likely pathway, and feeding studies supported the hypothesis that the chain length of PKS metabolites may be under precise control of KS and PT domains...
  10. Shulse C, Allen E. Diversity and distribution of microbial long-chain fatty acid biosynthetic genes in the marine environment. Environ Microbiol. 2011;13:684-95 pubmed publisher
    ..These findings reveal a widespread capacity for long-chain fatty acid production in marine microorganisms, including biosynthetic pathways not yet characterized. ..
  11. Arthur J, Perez Chanona E, Muhlbauer M, Tomkovich S, Uronis J, Fan T, et al. Intestinal inflammation targets cancer-inducing activity of the microbiota. Science. 2012;338:120-3 pubmed publisher
    ..This suggests that in mice, colitis can promote tumorigenesis by altering microbial composition and inducing the expansion of microorganisms with genotoxic capabilities. ..
  12. Mohanty D, Sankaranarayanan R, Gokhale R. Fatty acyl-AMP ligases and polyketide synthases are unique enzymes of lipid biosynthetic machinery in Mycobacterium tuberculosis. Tuberculosis (Edinb). 2011;91:448-55 pubmed publisher
    ..biochemical and structural studies in lipid biosynthesis that have established functional role of polyketide synthases (PKSs) and fatty acyl-AMP ligases (FAALs)...
  13. Feng Z, Kallifidas D, Brady S. Functional analysis of environmental DNA-derived type II polyketide synthases reveals structurally diverse secondary metabolites. Proc Natl Acad Sci U S A. 2011;108:12629-34 pubmed publisher
    ..The large-scale functional screening of eDNA clones should be a productive strategy for generating structurally previously uncharacterized chemical entities for use in future drug development efforts. ..
  14. Siegl A, Kamke J, Hochmuth T, Piel J, Richter M, Liang C, et al. Single-cell genomics reveals the lifestyle of Poribacteria, a candidate phylum symbiotically associated with marine sponges. ISME J. 2011;5:61-70 pubmed publisher
    ..The cell wall is of Gram-negative origin. The Poribacteria produce at least two polyketide synthases (PKSs), one of which is the sponge-specific Sup-type PKS...
  15. Wu Y, Kang Q, Shen Y, Su W, Bai L. Cloning and functional analysis of the naphthomycin biosynthetic gene cluster in Streptomyces sp. CS. Mol Biosyst. 2011;7:2459-69 pubmed publisher
    ..The information presented here expands our understanding of the biosynthesis of naphthalenic ansamycins, and may pave the way for engineering ansamacrolactams with improved pharmaceutical properties. ..
  16. Yuzawa S, Kapur S, Cane D, Khosla C. Role of a conserved arginine residue in linkers between the ketosynthase and acyltransferase domains of multimodular polyketide synthases. Biochemistry. 2012;51:3708-10 pubmed publisher
    The role of interdomain linkers in modular polyketide synthases is poorly understood...
  17. Shulse C, Allen E. Widespread occurrence of secondary lipid biosynthesis potential in microbial lineages. PLoS ONE. 2011;6:e20146 pubmed publisher
    ..designated pfaEABCD, encode large, multi-domain protein complexes akin to type I iterative fatty acid and polyketide synthases, herein referred to as "Pfa synthases"...
  18. Gehret J, Gu L, Gerwick W, Wipf P, Sherman D, Smith J. Terminal alkene formation by the thioesterase of curacin A biosynthesis: structure of a decarboxylating thioesterase. J Biol Chem. 2011;286:14445-54 pubmed publisher
    ..Formation of a sulfate leaving group as a biosynthetic strategy to facilitate acyl chain decarboxylation is of potential value as a route to hydrocarbon biofuels. ..
  19. Akey D, Razelun J, Tehranisa J, Sherman D, Gerwick W, Smith J. Crystal structures of dehydratase domains from the curacin polyketide biosynthetic pathway. Structure. 2010;18:94-105 pubmed publisher
    Modular polyketide synthases (PKS) make novel natural products through a series of preprogrammed chemical steps catalyzed by an assembly line of multidomain modules...
  20. Pavlidou M, Pross E, Musiol E, Kulik A, Wohlleben W, Weber T. The phosphopantetheinyl transferase KirP activates the ACP and PCP domains of the kirromycin NRPS/PKS of Streptomyces collinus Tü 365. FEMS Microbiol Lett. 2011;319:26-33 pubmed publisher
    ..biosynthesis of complex secondary metabolites such as the antibiotic kirromycin are catalyzed by modular polyketide synthases (PKS) and/or nonribosomal peptide synthetases (NRPS)...
  21. Campbell C, Vederas J. Biosynthesis of lovastatin and related metabolites formed by fungal iterative PKS enzymes. Biopolymers. 2010;93:755-63 pubmed publisher
    ..This review examines the biosynthesis of lovastatin, as well as of compactin, equisetin, cytochalasins, and solanapyrones, which are other structurally related polyketides that appear to utilize a Diels-Alderase. ..
  22. Stepień Ł, Gromadzka K, Chełkowski J. Polymorphism of mycotoxin biosynthetic genes among Fusarium equiseti isolates from Italy and Poland. J Appl Genet. 2012;53:227-36 pubmed publisher
    ..Italy and Poland) was evaluated by analysing the translation elongation factor 1? (tef-1?) sequences, two polyketide synthases from the ZEA biosynthetic pathway (PKS13 and PKS4) and the TRI5 gene from the trichothecene biosynthetic ..
  23. Olano C, Mendez C, Salas J. Post-PKS tailoring steps in natural product-producing actinomycetes from the perspective of combinatorial biosynthesis. Nat Prod Rep. 2010;27:571-616 pubmed
  24. Tobias N, Seemann T, Pidot S, Porter J, Marsollier L, Marion E, et al. Mycolactone gene expression is controlled by strong SigA-like promoters with utility in studies of Mycobacterium ulcerans and buruli ulcer. PLoS Negl Trop Dis. 2009;3:e553 pubmed publisher
    ..ulcerans-GFP, a strain in which fluorescence and toxin gene expression are linked, thus providing a tool for studying Buruli ulcer pathogenesis and potential transmission to humans. ..
  25. Ma S, Li J, Choi J, Zhou H, Lee K, Moorthie V, et al. Complete reconstitution of a highly reducing iterative polyketide synthase. Science. 2009;326:589-92 pubmed publisher
    Highly reducing iterative polyketide synthases are large, multifunctional enzymes that make important metabolites in fungi, such as lovastatin, a cholesterol-lowering drug from Aspergillus terreus...
  26. Zhang H, Wang Y, Wu J, Skalina K, Pfeifer B. Complete biosynthesis of erythromycin A and designed analogs using E. coli as a heterologous host. Chem Biol. 2010;17:1232-40 pubmed publisher
    ..Success establishes E. coli as a viable option for the heterologous production of erythromycin A and more broadly as a platform for the directed production of erythromycin analogs...
  27. Chemler J, Buchholz T, Geders T, Akey D, Rath C, Chlipala G, et al. Biochemical and structural characterization of germicidin synthase: analysis of a type III polyketide synthase that employs acyl-ACP as a starter unit donor. J Am Chem Soc. 2012;134:7359-66 pubmed publisher
    ..This investigation provides new and surprising information about the interactions between type III PKSs and ACPs that will facilitate the construction of engineered systems for production of novel polyketides. ..
  28. Zheng J, Taylor C, Piasecki S, Keatinge Clay A. Structural and functional analysis of A-type ketoreductases from the amphotericin modular polyketide synthase. Structure. 2010;18:913-22 pubmed publisher
    ..Together, these results highlight the possibility of region-specific modification of polyketides through active site engineering of KRs. ..
  29. Horsman G, Chen Y, Thorson J, Shen B. Polyketide synthase chemistry does not direct biosynthetic divergence between 9- and 10-membered enediynes. Proc Natl Acad Sci U S A. 2010;107:11331-5 pubmed publisher
    ..Previous work identified enediyne-specific polyketide synthases (PKSEs) that can be phylogenetically distinguished as being involved in 9- versus 10-membered enediyne ..
  30. Piasecki S, Taylor C, Detelich J, Liu J, Zheng J, Komsoukaniants A, et al. Employing modular polyketide synthase ketoreductases as biocatalysts in the preparative chemoenzymatic syntheses of diketide chiral building blocks. Chem Biol. 2011;18:1331-40 pubmed publisher
    ..Several biocatalytic reactions were scaled up to yield more than 100 mg of product. These syntheses demonstrate the ability of PKS enzymes to economically and greenly generate diverse chiral building blocks on a preparative scale. ..
  31. Anand S, Mohanty D. Modeling holo-ACP:DH and holo-ACP:KR complexes of modular polyketide synthases: a docking and molecular dynamics study. BMC Struct Biol. 2012;12:10 pubmed publisher
    Modular polyketide synthases are multifunctional megasynthases which biosynthesize a variety of secondary metabolites using various combinations of dehydratase (DH), ketoreductase (KR) and enoyl-reductase (ER) domains...
  32. Weber T, Rausch C, Lopez P, Hoof I, Gaykova V, Huson D, et al. CLUSEAN: a computer-based framework for the automated analysis of bacterial secondary metabolite biosynthetic gene clusters. J Biotechnol. 2009;140:13-7 pubmed
    ..tools, like BLAST and HMMer, with specific tools for the identification of the functional domains and motifs in nonribosomal peptide synthetases (NRPS)/type I polyketide synthases (PKS) and the prediction of specificities of NRPS.
  33. Ouyang Y, Wu H, Xie L, Wang G, Dai S, Chen M, et al. A method to type the potential angucycline producers in actinomycetes isolated from marine sponges. Antonie Van Leeuwenhoek. 2011;99:807-15 pubmed publisher
    ..The specific primer set targeting the cyclase can be used to identify putative angucycline producers among marine actinobacteria, and aid in the discovery of novel angucyclines...
  34. Boettger D, Bergmann H, Kuehn B, Shelest E, Hertweck C. Evolutionary imprint of catalytic domains in fungal PKS-NRPS hybrids. Chembiochem. 2012;13:2363-73 pubmed publisher
    ..These findings shed new light on the complex code of this emerging class of multifunctional enzymes and will greatly facilitate future combinatorial biosynthesis and pathway engineering approaches towards natural product analogues. ..
  35. Dalmais B, Schumacher J, Moraga J, Le Pêcheur P, Tudzynski B, Collado I, et al. The Botrytis cinerea phytotoxin botcinic acid requires two polyketide synthases for production and has a redundant role in virulence with botrydial. Mol Plant Pathol. 2011;12:564-79 pubmed publisher
    ..However, double mutants that do not produce botcinic acid or botrydial (bcpks6?bcbot2?) exhibit markedly reduced virulence. Hence, a redundant role of botrydial and botcinic acid in the virulence of B. cinerea has been demonstrated...
  36. Boettger D, Hertweck C. Molecular diversity sculpted by fungal PKS-NRPS hybrids. Chembiochem. 2013;14:28-42 pubmed publisher
  37. Fisch K, Bakeer W, Yakasai A, Song Z, Pedrick J, Wasil Z, et al. Rational domain swaps decipher programming in fungal highly reducing polyketide synthases and resurrect an extinct metabolite. J Am Chem Soc. 2011;133:16635-41 pubmed publisher
    The mechanism of programming of iterative highly reducing polyketide synthases remains one of the key unsolved problems of secondary metabolism...
  38. Wong F, Chen A, Cane D, Khosla C. Protein-protein recognition between acyltransferases and acyl carrier proteins in multimodular polyketide synthases. Biochemistry. 2010;49:95-102 pubmed publisher
    Acyltransferase (AT) domains of multimodular polyketide synthases are the primary gatekeepers for stepwise incorporation of building blocks into a growing polyketide chain...
  39. Wakimoto T, Mori T, Morita H, Abe I. Cytotoxic tetramic acid derivative produced by a plant type-III polyketide synthase. J Am Chem Soc. 2011;133:4746-9 pubmed publisher
    ..Remarkably, the novel tetramic acid dimer D-5 formed from D-phenylalanoyl-CoA showed moderate antiproliferative activity against murine leukemia P388 cells. ..
  40. Wilson R, Kumar P, Parashar V, Vilchèze C, Veyron Churlet R, Freundlich J, et al. Antituberculosis thiophenes define a requirement for Pks13 in mycolic acid biosynthesis. Nat Chem Biol. 2013;9:499-506 pubmed publisher
    ..tuberculosis Pks13 is required for mycolic acid biosynthesis, validates it as a druggable target and demonstrates the therapeutic potential of simultaneously inhibiting multiple targets in the same biosynthetic pathway. ..
  41. Fewer D, Osterholm J, Rouhiainen L, Jokela J, Wahlsten M, Sivonen K. Nostophycin biosynthesis is directed by a hybrid polyketide synthase-nonribosomal peptide synthetase in the toxic cyanobacterium Nostoc sp. strain 152. Appl Environ Microbiol. 2011;77:8034-40 pubmed publisher
    ..Biosyntheses of nostophycin and microcystin resemble each other, but the phylogenetic analyses suggest that they are distantly related to one another...
  42. Crawford J, Townsend C. New insights into the formation of fungal aromatic polyketides. Nat Rev Microbiol. 2010;8:879-89 pubmed publisher
    ..a large family of bioactive natural products and are synthesized by the non-reducing group of iterative polyketide synthases (PKSs)...
  43. Lou L, Chen H, Cerny R, Li Y, Shen Y, Du L. Unusual activities of the thioesterase domain for the biosynthesis of the polycyclic tetramate macrolactam HSAF in Lysobacter enzymogenes C3. Biochemistry. 2012;51:4-6 pubmed publisher
    ..The iterative PKS-NRPS is found in all polycyclic tetramate macrolactam gene clusters, and the unusual activities of the TE may be common to this type of hybrid PKS-NRPS. ..
  44. Lou L, Qian G, Xie Y, Hang J, Chen H, Zaleta Rivera K, et al. Biosynthesis of HSAF, a tetramic acid-containing macrolactam from Lysobacter enzymogenes. J Am Chem Soc. 2011;133:643-5 pubmed publisher
    ..These results reveal a previously unrecognized biosynthetic mechanism for hybrid PK/NRP in prokaryotic organisms. ..
  45. Liew C, Sharff A, Kotaka M, Kong R, Sun H, Qureshi I, et al. Induced-fit upon ligand binding revealed by crystal structures of the hot-dog fold thioesterase in dynemicin biosynthesis. J Mol Biol. 2010;404:291-306 pubmed publisher
  46. Anand S, Prasad M, Yadav G, Kumar N, Shehara J, Ansari M, et al. SBSPKS: structure based sequence analysis of polyketide synthases. Nucleic Acids Res. 2010;38:W487-96 pubmed publisher
    b>Polyketide synthases (PKSs) catalyze biosynthesis of a diverse family of pharmaceutically important secondary metabolites...
  47. Mattheus W, Gao L, Herdewijn P, Landuyt B, Verhaegen J, Masschelein J, et al. Isolation and purification of a new kalimantacin/batumin-related polyketide antibiotic and elucidation of its biosynthesis gene cluster. Chem Biol. 2010;17:149-59 pubmed publisher
    ..This makes it a promising new therapeutic option to cope with multidrug-resistant clinical infections. ..
  48. Wattana amorn P, Williams C, Płoskoń E, Cox R, Simpson T, Crosby J, et al. Solution structure of an acyl carrier protein domain from a fungal type I polyketide synthase. Biochemistry. 2010;49:2186-93 pubmed publisher
  49. Della Sala G, Hochmuth T, Costantino V, Teta R, GERWICK W, Gerwick L, et al. Polyketide genes in the marine sponge Plakortis simplex: a new group of mono-modular type I polyketide synthases from sponge symbionts. Environ Microbiol Rep. 2013;5:809-18 pubmed publisher
    ..However, the precise biosynthetic role of the swf clusters remains unknown. ..
  50. Ziemert N, Podell S, Penn K, Badger J, Allen E, Jensen P. The natural product domain seeker NaPDoS: a phylogeny based bioinformatic tool to classify secondary metabolite gene diversity. PLoS ONE. 2012;7:e34064 pubmed publisher
    ..The results provide a rapid method to assess secondary metabolite biosynthetic gene diversity and richness in organisms or environments and a mechanism to identify genes that may be associated with uncharacterized biochemistry. ..
  51. Kapur S, Lowry B, Yuzawa S, Kenthirapalan S, Chen A, Cane D, et al. Reprogramming a module of the 6-deoxyerythronolide B synthase for iterative chain elongation. Proc Natl Acad Sci U S A. 2012;109:4110-5 pubmed publisher
    Multimodular polyketide synthases (PKSs) have an assembly line architecture in which a set of protein domains, known as a module, participates in one round of polyketide chain elongation and associated chemical modifications, after which ..
  52. Ahuja M, Chiang Y, Chang S, Praseuth M, Entwistle R, Sanchez J, et al. Illuminating the diversity of aromatic polyketide synthases in Aspergillus nidulans. J Am Chem Soc. 2012;134:8212-21 pubmed publisher
    ..This has allowed us to determine the products of eight NR-PKSs of Aspergillus nidulans, including seven novel compounds, as well as the NR-PKS genes required for the synthesis of the toxins alternariol (8) and cichorine (19)...
  53. Zheng J, Keatinge Clay A. Structural and functional analysis of C2-type ketoreductases from modular polyketide synthases. J Mol Biol. 2011;410:105-17 pubmed publisher
    The process by which ?-stereocenters of polyketide intermediates are set by modular polyketide synthases (PKSs) when condensation is not immediately followed by reduction is mysterious...