peptide synthases


Summary: Ligases that catalyze the joining of adjacent AMINO ACIDS by the formation of carbon-nitrogen bonds between their carboxylic acid groups and amine groups.

Top Publications

  1. Christoph D, Asuncion B, Mascaux C, Tran C, Lu X, Wynes M, et al. Folylpoly-glutamate synthetase expression is associated with tumor response and outcome from pemetrexed-based chemotherapy in malignant pleural mesothelioma. J Thorac Oncol. 2012;7:1440-8 pubmed
    ..Prospective evaluation of FPGS and TS expressions and their prognostic/predictive power in MPM patients is warranted. ..
  2. Ikegami K, Sato S, Nakamura K, Ostrowski L, Setou M. Tubulin polyglutamylation is essential for airway ciliary function through the regulation of beating asymmetry. Proc Natl Acad Sci U S A. 2010;107:10490-5 pubmed publisher
    ..Our findings provide evidence that tubulin glutamylation is essential for ciliary function through the regulation of beating asymmetry, and provides insight into the molecular basis underlying the beating asymmetry. ..
  3. Felnagle E, Barkei J, Park H, Podevels A, McMahon M, Drott D, et al. MbtH-like proteins as integral components of bacterial nonribosomal peptide synthetases. Biochemistry. 2010;49:8815-7 pubmed publisher
    ..Using MbtH-like proteins from three separate NRPS systems, we show that these proteins copurify with the NRPSs and influence amino acid activation. As a consequence, MbtH-like proteins are integral components of NRPSs. ..
  4. Yang Y, Gao P, Liu Y, Ji X, Gan M, Guan Y, et al. A discovery of novel Mycobacterium tuberculosis pantothenate synthetase inhibitors based on the molecular mechanism of actinomycin D inhibition. Bioorg Med Chem Lett. 2011;21:3943-6 pubmed publisher
    ..5, respectively. Two inhibitors were identified with an IC(50) for pantothenate synthetase that was at least ten times better than that of ActD. ..
  5. Cao M, Geng W, Zhang W, Sun J, Wang S, Feng J, et al. Engineering of recombinant Escherichia coli cells co-expressing poly-?-glutamic acid (?-PGA) synthetase and glutamate racemase for differential yielding of ?-PGA. Microb Biotechnol. 2013;6:675-84 pubmed publisher
    ..This is the first report about co-expression of pgsBCA and racE from the two Bacillus strains, which will be of great value for the determination of the biosynthetic mechanism of ?-PGA. ..
  6. O HAGAN R, Piasecki B, Silva M, Phirke P, Nguyen K, Hall D, et al. The tubulin deglutamylase CCPP-1 regulates the function and stability of sensory cilia in C. elegans. Curr Biol. 2011;21:1685-94 pubmed publisher
    ..We propose that the neuronal degeneration caused by loss of CCP1 in mammals may represent a novel ciliopathy in which cilia are formed but not maintained, depriving the cell of cilia-based signal transduction. ..
  7. Guzman J, Wube A, Evangelopoulos D, Gupta A, Hufner A, Basavannacharya C, et al. Interaction of N-methyl-2-alkenyl-4-quinolones with ATP-dependent MurE ligase of Mycobacterium tuberculosis: antibacterial activity, molecular docking and inhibition kinetics. J Antimicrob Chemother. 2011;66:1766-72 pubmed publisher
    ..Therefore, they are considered as a starting point for the development of increased affinity MurE activity disruptors. ..
  8. Röttig M, Medema M, Blin K, Weber T, Rausch C, Kohlbacher O. NRPSpredictor2--a web server for predicting NRPS adenylation domain specificity. Nucleic Acids Res. 2011;39:W362-7 pubmed publisher
    ..84. The service is available at ..
  9. Balibar C, Hollis Symynkywicz M, Tao J. Pantethine rescues phosphopantothenoylcysteine synthetase and phosphopantothenoylcysteine decarboxylase deficiency in Escherichia coli but not in Pseudomonas aeruginosa. J Bacteriol. 2011;193:3304-12 pubmed publisher
    ..coli and coaX in P. aeruginosa. ..

More Information


  1. Caboche S, Leclère V, Pupin M, Kucherov G, Jacques P. Diversity of monomers in nonribosomal peptides: towards the prediction of origin and biological activity. J Bacteriol. 2010;192:5143-50 pubmed publisher
  2. Zidar N, Tomasić T, Sink R, Rupnik V, Kovac A, Turk S, et al. Discovery of novel 5-benzylidenerhodanine and 5-benzylidenethiazolidine-2,4-dione inhibitors of MurD ligase. J Med Chem. 2010;53:6584-94 pubmed publisher
  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. Zhang W, Heemstra J, Walsh C, Imker H. Activation of the pacidamycin PacL adenylation domain by MbtH-like proteins. Biochemistry. 2010;49:9946-7 pubmed publisher
    ..We also demonstrate that adenylation can be stimulated not only by cognate MbtH-like proteins but also by homologues from disparate natural product pathways. ..
  5. Liu F, Sun W, Su F, Zhou K, Li Z. Draft genome sequence of the sponge-associated strain Bacillus atrophaeus C89, a potential producer of marine drugs. J Bacteriol. 2012;194:4454 pubmed publisher
    ..Here, we present a 4.2-Mb assembly of its genome. The nonribosomal peptide synthetases (NRPSs) make it possible to produce the bioactive compounds...
  6. Belin P, Moutiez M, Lautru S, Seguin J, Pernodet J, Gondry M. The nonribosomal synthesis of diketopiperazines in tRNA-dependent cyclodipeptide synthase pathways. Nat Prod Rep. 2012;29:961-79 pubmed publisher
    ..This review includes a comprehensive description of the state of the art for CDPS-dependent pathways, and highlights the ways in which this knowledge could be used to increase the diversity of natural DKPs by pathway engineering. ..
  7. Osman K, Evangelopoulos D, Basavannacharya C, Gupta A, McHugh T, Bhakta S, et al. An antibacterial from Hypericum acmosepalum inhibits ATP-dependent MurE ligase from Mycobacterium tuberculosis. Int J Antimicrob Agents. 2012;39:124-9 pubmed publisher
    ..tuberculosis, a crucial enzyme in the cytoplasmic steps of peptidoglycan biosynthesis. Hyperenone A inhibited MurE selectively, whereas hypercalin B did not have any effect on enzyme activity...
  8. Hodges T, Slattery M, Olson J. Unique actinomycetes from marine caves and coral reef sediments provide novel PKS and NRPS biosynthetic gene clusters. Mar Biotechnol (NY). 2012;14:270-80 pubmed publisher
  9. Cao M, Geng W, Liu L, Song C, Xie H, Guo W, et al. Glutamic acid independent production of poly-?-glutamic acid by Bacillus amyloliquefaciens LL3 and cloning of pgsBCA genes. Bioresour Technol. 2011;102:4251-7 pubmed publisher
  10. 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 ..
  11. Zhou K, Zhang X, Zhang F, Li Z. Phylogenetically diverse cultivable fungal community and polyketide synthase (PKS), non-ribosomal peptide synthase (NRPS) genes associated with the South China Sea sponges. Microb Ecol. 2011;62:644-54 pubmed publisher
    ..This study extended our knowledge of sponge-associated fungal phylogenetic diversity and their potential roles in the chemical defense...
  12. 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...
  13. Boettger D, Hertweck C. Molecular diversity sculpted by fungal PKS-NRPS hybrids. Chembiochem. 2013;14:28-42 pubmed publisher
  14. 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. ..
  15. Szyk A, Deaconescu A, Piszczek G, Roll Mecak A. Tubulin tyrosine ligase structure reveals adaptation of an ancient fold to bind and modify tubulin. Nat Struct Mol Biol. 2011;18:1250-8 pubmed publisher
  16. Imker H, Krahn D, Clerc J, Kaiser M, Walsh C. N-acylation during glidobactin biosynthesis by the tridomain nonribosomal peptide synthetase module GlbF. Chem Biol. 2010;17:1077-83 pubmed publisher
  17. Pathak N, Austin C, Drummond I. Tubulin tyrosine ligase-like genes ttll3 and ttll6 maintain zebrafish cilia structure and motility. J Biol Chem. 2011;286:11685-95 pubmed publisher
  18. 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
    ..Thus, KirP is very flexible in terms of both CoA substrate and carrier protein specificity. Our results indicate that KirP is the main PPTases that activates the carrier proteins in kirromycin biosynthesis. ..
  19. Gallo A, Bruno K, Solfrizzo M, Perrone G, Mulè G, Visconti A, et al. New insight into the ochratoxin A biosynthetic pathway through deletion of a nonribosomal peptide synthetase gene in Aspergillus carbonarius. Appl Environ Microbiol. 2012;78:8208-18 pubmed publisher
    ..carbonarius and that ochratoxin ? is a product of hydrolysis of OTA, giving an interesting new insight into the biosynthetic pathway of the toxin. ..
  20. Garcia I, Vior N, Brana A, González Sabín J, Rohr J, Morís F, et al. Elucidating the biosynthetic pathway for the polyketide-nonribosomal peptide collismycin A: mechanism for formation of the 2,2'-bipyridyl ring. Chem Biol. 2012;19:399-413 pubmed publisher
  21. Owen J, Copp J, Ackerley D. Rapid and flexible biochemical assays for evaluating 4'-phosphopantetheinyl transferase activity. Biochem J. 2011;436:709-17 pubmed publisher
    ..T.C.C.6633, PcpS of Pseudomonas aeruginosa PAO1, and the putative PPTase PP1183 of Ps. putida KT2440. We also demonstrate the utility of this system for discovery and characterization of PPTase inhibitors. ..
  22. Seguin J, Moutiez M, Li Y, Belin P, Lecoq A, Fonvielle M, et al. Nonribosomal peptide synthesis in animals: the cyclodipeptide synthase of Nematostella. Chem Biol. 2011;18:1362-8 pubmed publisher
    ..They also raise questions about the biological roles of the cyclodipeptides produced in bacteria and eukaryotes. ..
  23. Kubo T, Yagi T, Kamiya R. Tubulin polyglutamylation regulates flagellar motility by controlling a specific inner-arm dynein that interacts with the dynein regulatory complex. Cytoskeleton (Hoboken). 2012;69:1059-68 pubmed publisher
    ..Tubulin polyglutamylation thus may play a central role in the regulation of ciliary and flagellar motility. © 2012 Wiley Periodicals, Inc...
  24. Nishizawa T, Ueda A, Nakano T, Nishizawa A, Miura T, Asayama M, et al. Characterization of the locus of genes encoding enzymes producing heptadepsipeptide micropeptin in the unicellular cyanobacterium Microcystis. J Biochem. 2011;149:475-85 pubmed publisher
    ..Finally, a comparative bioinformatics analysis of the congenial gene cluster for depsipetide biosynthesis suggested the diversification and propagation of the NRPS genes in cyanobacteria. ..
  25. Vetting M, Hegde S, Blanchard J. The structure and mechanism of the Mycobacterium tuberculosis cyclodityrosine synthetase. Nat Chem Biol. 2010;6:797-9 pubmed publisher
  26. Vehar B, Hrast M, Kovac A, Konc J, Mariner K, Chopra I, et al. Ellipticines and 9-acridinylamines as inhibitors of D-alanine:D-alanine ligase. Bioorg Med Chem. 2011;19:5137-46 pubmed publisher
    ..Antimicrobial activity of the studied compounds was connected to membrane damage, making their development as antibacterial drug candidates unlikely unless analogues devoid of this nonspecific effect can be discovered. ..
  27. Kimura Y, Kurabe N, Ikegami K, Tsutsumi K, Konishi Y, Kaplan O, et al. Identification of tubulin deglutamylase among Caenorhabditis elegans and mammalian cytosolic carboxypeptidases (CCPs). J Biol Chem. 2010;285:22936-41 pubmed publisher
    ..Together, these data from two evolutionarily divergent systems identify C. elegans CCPP-6 and its mammalian ortholog CCP5 as a tubulin deglutamylase. ..
  28. Qiao K, Chooi Y, Tang Y. Identification and engineering of the cytochalasin gene cluster from Aspergillus clavatus NRRL 1. Metab Eng. 2011;13:723-32 pubmed publisher
    ..Our results not only shed light on the biosynthesis of cytochalasins, but also provided genetic tools for increasing and engineering the production. ..
  29. Giessen T, von Tesmar A, Marahiel M. Insights into the generation of structural diversity in a tRNA-dependent pathway for highly modified bioactive cyclic dipeptides. Chem Biol. 2013;20:828-38 pubmed publisher
  30. Basavannacharya C, Moody P, Munshi T, Cronin N, Keep N, Bhakta S. Essential residues for the enzyme activity of ATP-dependent MurE ligase from Mycobacterium tuberculosis. Protein Cell. 2010;1:1011-22 pubmed publisher
    ..Since ATP-dependent MurE ligase is a novel drug target, the understanding of its function may lead to development of novel inhibitors against resistant forms of M. tuberculosis. ..
  31. 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. ..
  32. Hou J, Robbel L, Marahiel M. Identification and characterization of the lysobactin biosynthetic gene cluster reveals mechanistic insights into an unusual termination module architecture. Chem Biol. 2011;18:655-64 pubmed publisher
    ..Biochemical characterization of the individual thioesterases in vitro provides evidence that solely penultimate thioesterase domain mediates the cyclization and simultaneous release of lysobactin. ..
  33. Prieto C, Garcia Estrada C, Lorenzana D, Martín J. NRPSsp: non-ribosomal peptide synthase substrate predictor. Bioinformatics. 2012;28:426-7 pubmed publisher
    ..The database and the predictor are freely available on an easy-to-use website at Supplementary data is available at Bioinformatics online. ..
  34. Tomasić T, Zidar N, Sink R, Kovac A, Blanot D, Contreras Martel C, et al. Structure-based design of a new series of D-glutamic acid based inhibitors of bacterial UDP-N-acetylmuramoyl-L-alanine:D-glutamate ligase (MurD). J Med Chem. 2011;54:4600-10 pubmed publisher
    ..Compounds 73-75, with IC(50) values in the low micromolar range, represent the most potent D-Glu-based MurD inhibitors reported to date. ..
  35. Pistorius D, Muller R. Discovery of the rhizopodin biosynthetic gene cluster in Stigmatella aurantiaca Sg a15 by genome mining. Chembiochem. 2012;13:416-26 pubmed publisher
    ..By matching with our in-house database of myxobacterial secondary metabolites, this compound was identified as rhizopodin. A detailed analysis of the rhizopodin biosynthetic machinery is presented in this manuscript...
  36. 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. ..
  37. Sauguet L, Moutiez M, Li Y, Belin P, Seguin J, Le Du M, et al. Cyclodipeptide synthases, a family of class-I aminoacyl-tRNA synthetase-like enzymes involved in non-ribosomal peptide synthesis. Nucleic Acids Res. 2011;39:4475-89 pubmed publisher
    ..These findings provide insight into the molecular bases of the interactions between CDPSs and their aa-tRNAs substrates, and the catalytic mechanism used by CDPSs to achieve the non-ribosomal synthesis of cyclodipeptides. ..
  38. Berezniuk I, Vu H, Lyons P, Sironi J, Xiao H, Burd B, et al. Cytosolic carboxypeptidase 1 is involved in processing ?- and ?-tubulin. J Biol Chem. 2012;287:6503-17 pubmed publisher
    ..Taken together, these results demonstrate a role for CCP1 in the processing of Glu residues from ?- as well as ?-tubulin in vitro and in vivo. ..
  39. Guzman J, Gupta A, Evangelopoulos D, Basavannacharya C, Pabon L, Plazas E, et al. Anti-tubercular screening of natural products from Colombian plants: 3-methoxynordomesticine, an inhibitor of MurE ligase of Mycobacterium tuberculosis. J Antimicrob Chemother. 2010;65:2101-7 pubmed publisher
    ..The alkaloid showed MurE inhibition and is considered an initial hit for exploring related chemical space. ..
  40. Bruning J, Murillo A, Chacon O, Barletta R, Sacchettini J. Structure of the Mycobacterium tuberculosis D-alanine:D-alanine ligase, a target of the antituberculosis drug D-cycloserine. Antimicrob Agents Chemother. 2011;55:291-301 pubmed publisher
    ..Moreover, DCS binding is tighter at higher ATP concentrations. The crystal structure illustrates potential drugable sites that may result in the development of more-effective Ddl inhibitors. ..
  41. Silvestre H, Blundell T, Abell C, Ciulli A. Integrated biophysical approach to fragment screening and validation for fragment-based lead discovery. Proc Natl Acad Sci U S A. 2013;110:12984-9 pubmed publisher
    ..Our multibiophysical approach identified three distinct binding sites for fragments and laid a solid foundation for successful structure-based elaboration into potent inhibitors. ..
  42. Prosser G, de Carvalho L. Kinetic mechanism and inhibition of Mycobacterium tuberculosis D-alanine:D-alanine ligase by the antibiotic D-cycloserine. FEBS J. 2013;280:1150-66 pubmed publisher
    ..5), suggesting that DCS binds optimally in the zwitterionic form. The results of this study may assist in the design and development of novel Ddl-specific inhibitors for use as anti-mycobacterial agents...
  43. Abrahams G, Kumar A, Savvi S, Hung A, Wen S, Abell C, et al. Pathway-selective sensitization of Mycobacterium tuberculosis for target-based whole-cell screening. Chem Biol. 2012;19:844-54 pubmed publisher
    ..These findings illustrate the power of TB-WCS as a tool for tuberculosis drug discovery. ..
  44. Barreteau H, Sosič I, Turk S, Humljan J, Tomasić T, Zidar N, et al. MurD enzymes from different bacteria: evaluation of inhibitors. Biochem Pharmacol. 2012;84:625-32 pubmed publisher
    ..coli MurD inhibitors appeared less efficient against the four other orthologues. This divergent result can be explained by the differences in amino acid sequences and topologies of the active sites of the MurD ligases studied. ..
  45. Rokni Zadeh H, Li W, Sánchez Rodríguez A, Sinnaeve D, Rozenski J, Martins J, et al. Genetic and functional characterization of cyclic lipopeptide white-line-inducing principle (WLIP) production by rice rhizosphere isolate Pseudomonas putida RW10S2. Appl Environ Microbiol. 2012;78:4826-34 pubmed publisher
  46. Galm U, Wendt Pienkowski E, Wang L, Huang S, Unsin C, Tao M, et al. Comparative analysis of the biosynthetic gene clusters and pathways for three structurally related antitumor antibiotics: bleomycin, tallysomycin, and zorbamycin. J Nat Prod. 2011;74:526-36 pubmed publisher
  47. Kraas F, Helmetag V, Wittmann M, Strieker M, Marahiel M. Functional dissection of surfactin synthetase initiation module reveals insights into the mechanism of lipoinitiation. Chem Biol. 2010;17:872-80 pubmed publisher
  48. Hopkinson B, Barbeau K. Iron transporters in marine prokaryotic genomes and metagenomes. Environ Microbiol. 2012;14:114-28 pubmed publisher
    ..Our results are largely consistent with current knowledge of iron speciation in the ocean, but suggest that in certain niches the ability to acquire siderophores and/or haem iron chelates is beneficial...
  49. Simcic M, Hodoscek M, Humljan J, Kristan K, Urleb U, Kocjan D, et al. NMR and molecular dynamics study of the binding mode of naphthalene-N-sulfonyl-D-glutamic acid derivatives: novel MurD ligase inhibitors. J Med Chem. 2009;52:2899-908 pubmed publisher
    ..Conformational flexibility not evident in the crystal structures may have an effect on ligand-binding site adaptability, and this is probably one of the important reasons for the only moderate activity of novel derivatives. ..
  50. Fewer D, Jokela J, Rouhiainen L, Wahlsten M, Koskenniemi K, Stal L, et al. The non-ribosomal assembly and frequent occurrence of the protease inhibitors spumigins in the bloom-forming cyanobacterium Nodularia spumigena. Mol Microbiol. 2009;73:924-37 pubmed publisher
    ..Our results demonstrate that bloom-forming N. spumigena strains produce a cocktail of enzyme inhibitors, which may explain in part the ecological success of this cyanobacterium in brackish water bodies worldwide...
  51. Nocek B, Evdokimova E, Proudfoot M, Kudritska M, Grochowski L, White R, et al. Structure of an amide bond forming F(420):gamma-glutamyl ligase from Archaeoglobus fulgidus -- a member of a new family of non-ribosomal peptide synthases. J Mol Biol. 2007;372:456-69 pubmed publisher
    ..We show that the enzyme adds a glutamate residue to both F(420)-0 and F(420)-1 in two distinct steps. CofE represents the first member of a new structural family of non-ribosomal peptide synthases.
  52. Janso J, Carter G. Biosynthetic potential of phylogenetically unique endophytic actinomycetes from tropical plants. Appl Environ Microbiol. 2010;76:4377-86 pubmed publisher
    ..These results suggest that tropical plants from New Guinea and the adjacent archipelago are hosts to unique endophytic actinomycetes that possess significant biosynthetic potential...
  53. Villet R, Fonvielle M, Busca P, Chemama M, Maillard A, Hugonnet J, et al. Idiosyncratic features in tRNAs participating in bacterial cell wall synthesis. Nucleic Acids Res. 2007;35:6870-83 pubmed
    ..The different modes of recognition of the acceptor stem indicate that specific inhibition of FemX(Wv) could be achieved by targeting the distal portion of tRNA(Ala) for the design of substrate analogues. ..