Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.


Logo for

Science 303 (5665): 1805-1810

Copyright © 2004 by the American Association for the Advancement of Science

Polyketide and Nonribosomal Peptide Antibiotics: Modularity and Versatility

Christopher T. Walsh

Abstract: Polyketide (PK) and nonribosomal peptides (NRP), constructed on multimodular enzymatic assembly lines, often attain the conformations that establish biological activity by cyclization constraints introduced by tailoring enzymes. The dedicated tailoring enzymes are encoded by genes clustered with the assembly line genes for coordinated regulation. NRP heterocyclizations to thiazoles and oxazoles can occur on the elongating framework of acyl-S enzyme intermediates, whereas tandem cyclic PK polyether formation of furans and pyrans can be initiated by post–assembly line epoxidases. Macrocyclizations of NRP, PK, and hybrid NRP-PK scaffolds occur in assembly line chain termination steps. Post–assembly line cascades of enzymatic oxidations also create cross-linked and cyclized architectures that generate the mature scaffolds of natural product antibiotics. The modularity of the natural product assembly lines and permissivity of tailoring enzymes offer prospects for reprogramming to create novel antibiotics with optimized properties.

Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.

E-mail: christopher_walsh{at}

FK506 Maturation Involves a Cytochrome P450 Protein-Catalyzed Four-Electron C-9 Oxidation in Parallel with a C-31 O-Methylation.
D. Chen, L. Zhang, B. Pang, J. Chen, Z. Xu, I. Abe, and W. Liu (2013)
J. Bacteriol. 195, 1931-1939
   Abstract »    Full Text »    PDF »
Direct surfactin-gramicidin S antagonism supports detoxification in mixed producer cultures of Bacillus subtilis and Aneurinibacillus migulanus.
M. Rautenbach, H. A. Eyeghe-Bickong, N. M. Vlok, M. Stander, and A. de Beer (2012)
Microbiology 158, 3072-3082
   Abstract »    Full Text »    PDF »
Templating a Molecular Tug-of-War.
M. R. Diehl (2012)
Science 338, 626-627
   Abstract »    Full Text »    PDF »
Enzymatic resistance to the lipopeptide surfactin as identified through imaging mass spectrometry of bacterial competition.
B. C. Hoefler, K. V. Gorzelnik, J. Y. Yang, N. Hendricks, P. C. Dorrestein, and P. D. Straight (2012)
PNAS 109, 13082-13087
   Abstract »    Full Text »    PDF »
Crystal Structure of the Acyltransferase Domain of the Iterative Polyketide Synthase in Enediyne Biosynthesis.
C. W. Liew, M. Nilsson, M. W. Chen, H. Sun, T. Cornvik, Z.-X. Liang, and J. Lescar (2012)
J. Biol. Chem. 287, 23203-23215
   Abstract »    Full Text »    PDF »
Genetic Screening Strategy for Rapid Access to Polyether Ionophore Producers and Products in Actinomycetes.
H. Wang, N. Liu, L. Xi, X. Rong, J. Ruan, and Y. Huang (2011)
Appl. Envir. Microbiol. 77, 3433-3442
   Abstract »    Full Text »    PDF »
Catalysis at the Intersection of Biology, Chemistry, and Medicine.
C. T. Walsh (2010)
J. Biol. Chem. 285, 29681-29689
   Full Text »    PDF »
Characterization of a Novel Type of Oxidative Decarboxylase Involved in the Biosynthesis of the Styryl Moiety of Chondrochloren from an Acylated Tyrosine.
S. Rachid, O. Revermann, C. Dauth, U. Kazmaier, and R. Muller (2010)
J. Biol. Chem. 285, 12482-12489
   Abstract »    Full Text »    PDF »
Sequence-Based Analysis of Secondary-Metabolite Biosynthesis in Marine Actinobacteria.
E. A. Gontang, S. P. Gaudencio, W. Fenical, and P. R. Jensen (2010)
Appl. Envir. Microbiol. 76, 2487-2499
   Abstract »    Full Text »    PDF »
Heterologous Expression of the Oxytetracycline Biosynthetic Pathway in Myxococcus xanthus.
D. C. Stevens, M. R. Henry, K. A. Murphy, and C. N. Boddy (2010)
Appl. Envir. Microbiol. 76, 2681-2683
   Abstract »    Full Text »    PDF »
Role of Bacillus subtilis BacB in the Synthesis of Bacilysin.
M. Rajavel, A. Mitra, and B. Gopal (2009)
J. Biol. Chem. 284, 31882-31892
   Abstract »    Full Text »    PDF »
Complete Reconstitution of a Highly Reducing Iterative Polyketide Synthase.
S. M. Ma, J. W.-H. Li, J. W. Choi, H. Zhou, K. K. M. Lee, V. A. Moorthie, X. Xie, J. T. Kealey, N. A. Da Silva, J. C. Vederas, et al. (2009)
Science 326, 589-592
   Abstract »    Full Text »    PDF »
A ketoreductase domain in the PksJ protein of the bacillaene assembly line carries out both {alpha}- and {beta}-ketone reduction during chain growth.
C. T. Calderone, S. B. Bumpus, N. L. Kelleher, C. T. Walsh, and N. A. Magarvey (2008)
PNAS 105, 12809-12814
   Abstract »    Full Text »    PDF »
Crystal Structure of the Termination Module of a Nonribosomal Peptide Synthetase.
A. Tanovic, S. A. Samel, L.-O. Essen, and M. A. Marahiel (2008)
Science 321, 659-663
   Abstract »    Full Text »    PDF »
A phosphopantetheinylating polyketide synthase producing a linear polyene to initiate enediyne antitumor antibiotic biosynthesis.
J. Zhang, S. G. Van Lanen, J. Ju, W. Liu, P. C. Dorrestein, W. Li, N. L. Kelleher, and B. Shen (2008)
PNAS 105, 1460-1465
   Abstract »    Full Text »    PDF »
Crystal Structure of the ECH2 Catalytic Domain of CurF from Lyngbya majuscula: INSIGHTS INTO A DECARBOXYLASE INVOLVED IN POLYKETIDE CHAIN -BRANCHING.
T. W. Geders, L. Gu, J. C. Mowers, H. Liu, W. H. Gerwick, K. Hakansson, D. H. Sherman, and J. L. Smith (2007)
J. Biol. Chem. 282, 35954-35963
   Abstract »    Full Text »    PDF »
A singular enzymatic megacomplex from Bacillus subtilis.
P. D. Straight, M. A. Fischbach, C. T. Walsh, D. Z. Rudner, and R. Kolter (2007)
PNAS 104, 305-310
   Abstract »    Full Text »    PDF »
Escherichia coli induces DNA double-strand breaks in eukaryotic cells..
J.-P. Nougayrede, S. Homburg, F. Taieb, M. Boury, E. Brzuszkiewicz, G. Gottschalk, C. Buchrieser, J. Hacker, U. Dobrindt, and E. Oswald (2006)
Science 313, 848-851
   Abstract »    Full Text »    PDF »
The 2.7-A crystal structure of a 194-kDa homodimeric fragment of the 6-deoxyerythronolide B synthase.
Y. Tang, C.-Y. Kim, I. I. Mathews, D. E. Cane, and C. Khosla (2006)
PNAS 103, 11124-11129
   Abstract »    Full Text »    PDF »
Structure of UDP-N-acetylglucosamine acyltransferase with a bound antibacterial pentadecapeptide.
A. H. Williams, R. M. Immormino, D. T. Gewirth, and C. R. H. Raetz (2006)
PNAS 103, 10877-10882
   Abstract »    Full Text »    PDF »
Convergence of isoprene and polyketide biosynthetic machinery: Isoprenyl-S-carrier proteins in the pksX pathway of Bacillus subtilis.
C. T. Calderone, W. E. Kowtoniuk, N. L. Kelleher, C. T. Walsh, and P. C. Dorrestein (2006)
PNAS 103, 8977-8982
   Abstract »    Full Text »    PDF »
Conformational switches modulate protein interactions in peptide antibiotic synthetases..
A. Koglin, M. R. Mofid, F. Lohr, B. Schafer, V. V. Rogov, M.-M. Blum, T. Mittag, M. A. Marahiel, F. Bernhard, and V. Dotsch (2006)
Science 312, 273-276
   Abstract »    Full Text »    PDF »
Chemoenzymatic and Template-Directed Synthesis of Bioactive Macrocyclic Peptides.
J. Grunewald and M. A. Marahiel (2006)
Microbiol. Mol. Biol. Rev. 70, 121-146
   Abstract »    Full Text »    PDF »
Salicylate Biosynthesis: Overexpression, Purification, and Characterization of Irp9, a Bifunctional Salicylate Synthase from Yersinia enterocolitica.
O. Kerbarh, A. Ciulli, N. I. Howard, and C. Abell (2005)
J. Bacteriol. 187, 5061-5066
   Abstract »    Full Text »    PDF »
A Multidomain Fusion Protein in Listeria monocytogenes Catalyzes the Two Primary Activities for Glutathione Biosynthesis.
S. Gopal, I. Borovok, A. Ofer, M. Yanku, G. Cohen, W. Goebel, J. Kreft, and Y. Aharonowitz (2005)
J. Bacteriol. 187, 3839-3847
   Abstract »    Full Text »    PDF »
A comprehensive classification system for lipids.
E. Fahy, S. Subramaniam, H. A. Brown, C. K. Glass, A. H. Merrill Jr., R. C. Murphy, C. R. H. Raetz, D. W. Russell, Y. Seyama, W. Shaw, et al. (2005)
J. Lipid Res. 46, 839-862
   Abstract »    Full Text »    PDF »
Accessorizing natural products: Adding to nature's toolbox.
S. S. Lamb and G. D. Wright (2005)
PNAS 102, 519-520
   Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882