The Library

Identification of a bioactive 51-membered macrolide complex by activation of a silent polyketide synthase in Streptomyces ambofaciens

Tools

Laureti, L., Song, Lijiang, Huang, S., Corre, Christophe, Leblond, Pierre, Challis, Gregory L. and Aigle, B.. (2011) Identification of a bioactive 51-membered macrolide complex by activation of a silent polyketide synthase in Streptomyces ambofaciens. Proceedings of the National Academy of Sciences of the United States of America, Vol.108 (No.15). pp. 6258-6263. ISSN 0027-8424

Full text not available from this repository.

Abstract

There is a constant need for new and improved drugs to combat infectious diseases, cancer, and other major life-threatening conditions. The recent development of genomics-guided approaches for novel natural product discovery has stimulated renewed interest in the search for natural product-based drugs. Genome sequence analysis of Streptomyces ambofaciens ATCC23877 has revealed numerous secondary metabolite biosynthetic gene clusters, including a giant type I modular polyketide synthase (PKS) gene cluster, which is composed of 25 genes (nine of which encode PKSs) and spans almost 150 kb, making it one of the largest polyketide biosynthetic gene clusters described to date. The metabolic product(s) of this gene cluster are unknown, and transcriptional analyses showed that it is not expressed under laboratory growth conditions. The constitutive expression of a regulatory gene within the cluster, encoding a protein that is similar to Large ATP binding of the LuxR (LAL) family proteins, triggered the expression of the biosynthetic genes. This led to the identification of four 51-membered glycosylated macrolides, named stambomycins A–D as metabolic products of the gene cluster. The structures of these compounds imply several interesting biosynthetic features, including incorporation of unusual extender units into the polyketide chain and in trans hydroxylation of the growing polyketide chain to provide the hydroxyl group for macrolide formation. Interestingly, the stambomycins possess promising antiproliferative activity against human cancer cell lines. Database searches identify genes encoding LAL regulators within numerous cryptic biosynthetic gene clusters in actinomycete genomes, suggesting that constitutive expression of such pathway-specific activators represents a powerful approach for novel bioactive natural product discovery.

Item Type: Journal Article
Subjects: Q Science > QD Chemistry
Q Science > QR Microbiology
Divisions: Faculty of Science > Chemistry
Library of Congress Subject Headings (LCSH): Streptomyces, Polyketides, Biosynthesis, Antineoplastic agents, Genomics, Macrolide antibiotics
Journal or Publication Title: Proceedings of the National Academy of Sciences of the United States of America
Publisher: National Academy of Sciences
ISSN: 0027-8424
Official Date: 28 March 2011
Volume: Vol.108
Number: No.15
Page Range: pp. 6258-6263
Identification Number: 10.1073/pnas.1019077108
Status: Peer Reviewed
Publication Status: Published
Access rights to Published version: Restricted or Subscription Access
Funder: Sixth Framework Programme (European Commission) (FP6)
Grant number: FP6-5224 (FP6)
Conference Paper Type: Paper
References:

1. Bérdy J (2005) Bioactive microbial metabolites. J Antibiot (Tokyo) 58:1–
26.
2. Newman DJ, Cragg GM (2007) Natural products as sources of new drugs over the last
25 years. J Nat Prod 70:461–477.
3. Challis GL (2008) Mining microbial genomes for new natural products and biosynthetic
pathways. Microbiology 154:1555–1569.
4. Zerikly M, Challis GL (2009) Strategies for the discovery of new natural products by
genome mining. ChemBioChem 10:625–633.
5. Pinnert-Sindico S (1954) Une nouvelle espèce de Streptomyces productrice
d’antibiotiques: Streptomyces ambofaciens n. sp. caractères culturaux. Ann Inst
Pasteur (Paris) 87:702–707.
6. Juguet M, et al. (2009) An iterative nonribosomal peptide synthetase assembles the
pyrrole-amide antibiotic congocidine in Streptomyces ambofaciens. Chem Biol 16:
421–431.
7. Karray F, et al. (2007) Organization of the biosynthetic gene cluster for the macrolide
antibiotic spiramycin in Streptomyces ambofaciens. Microbiology 153:4111–4122.
8. Choulet F, et al. (2006) Evolution of the terminal regions of the Streptomyces linear
chromosome. Mol Biol Evol 23:2361–2369.
9. Barona-Gómez F, et al. (2006) Multiple biosynthetic and uptake systems mediate
siderophore-dependent iron acquisition in Streptomyces coelicolor A3(2) and
Streptomyces ambofaciens ATCC 23877. Microbiology 152:3355–3366.
10. Pang X, et al. (2004) Functional angucycline-like antibiotic gene cluster in the terminal
inverted repeats of the Streptomyces ambofaciens linear chromosome. Antimicrob
Agents Chemother 48:575–588.
11. Bunet R, et al. (2011) Characterization and manipulation of the pathway-specific
late regulator AlpW reveals Streptomyces ambofaciens as a new producer of
kinamycins. J Bacteriol 193:1142–1153.
12. Hertweck C (2009) The biosynthetic logic of polyketide diversity. Angew Chem Int Ed
Engl 48:4688–4716.
13. Yadav G, Gokhale RS, Mohanty D (2003) SEARCHPKS: A program for detection and
analysis of polyketide synthase domains. Nucleic Acids Res 31:3654–3658.
14. Bisang C, et al. (1999) A chain initiation factor common to both modular and aromatic
polyketide synthases. Nature 401:502–505.
15. Gokhale RS, Hunziker D, Cane DE, Khosla C (1999) Mechanism and specificity of the
terminal thioesterase domain from the erythromycin polyketide synthase. Chem Biol
6:117–125.
16. Callahan B, Thattai M, Shraiman BI (2009) Emergent gene order in a model of
modular polyketide synthases. Proc Natl Acad Sci USA 106:19410–19415.
17. Yadav G, Gokhale RS, Mohanty D (2003) Computational approach for prediction of
domain organization and substrate specificity of modular polyketide synthases.
J Mol Biol 328:335–363.
18. Keatinge-Clay AT (2007) A tylosin ketoreductase reveals how chirality is determined
in polyketides. Chem Biol 14:898–908.
19. Kwan DH, et al. (2008) Prediction and manipulation of the stereochemistry of
enoylreduction in modular polyketide synthases. Chem Biol 15:1231–1240.
20. Kamra P, Gokhale RS, Mohanty D (2005) SEARCHGTr: A program for analysis of
glycosyltransferases involved in glycosylation of secondary metabolites. Nucleic Acids
Res 33(Web Server issue):W220–225.
21. Hong JS, et al. (2007) Functional analysis of desVIII homologues involved in
glycosylation of macrolide antibiotics by interspecies complementation. Gene 386:
123–130.
22. Nguyen HC, et al. (2010) Glycosylation steps during spiramycin biosynthesis in
Streptomyces ambofaciens: Involvement of three glycosyltransferases and their
interplay with two auxiliary proteins. Antimicrob Agents Chemother 54:2830–2839.
23. Parajuli N, Basnet DB, Chan Lee H, Sohng JK, Liou K (2004) Genome analyses of
Streptomyces peucetius ATCC 27952 for the identification and comparison of
cytochrome P450 complement with other Streptomyces. Arch Biochem Biophys 425:
233–241.
24. Kim BS, Cropp TA, Beck BJ, Sherman DH, Reynolds KA (2002) Biochemical evidence
for an editing role of thioesterase II in the biosynthesis of the polyketide pikromycin.
J Biol Chem 277:48028–48034.
25. Pernodet JL, Alegre MT, Blondelet-Rouault MH, Guérineau M (1993) Resistance to
spiramycin in Streptomyces ambofaciens, the producer organism, involves at least
two different mechanisms. J Gen Microbiol 139:1003–1011.
26. De Schrijver A, De Mot R (1999) A subfamily of MalT-related ATP-dependent
regulators in the LuxR family. Microbiology 145:1287–1288.
27. Wilson DJ, Xue Y, Reynolds KA, Sherman DH (2001) Characterization and analysis of
the PikD regulatory factor in the pikromycin biosynthetic pathway of Streptomyces
venezuelae. J Bacteriol 183:3468–3475.
28. Kuscer E, et al. (2007) Roles of rapH and rapG in positive regulation of rapamycin
biosynthesis in Streptomyces hygroscopicus. J Bacteriol 189:4756–4763.
29. Wilkinson CJ, et al. (2002) Increasing the efficiency of heterologous promoters in
actinomycetes. J Mol Microbiol Biotechnol 4:417–426.
30. Ramu K, Shringarpure S, Cooperwood S, Beale JM, Williams JS (1994) 1H-NMR and
13C-NMR spectral assignments of spiramycins I and III. Pharm Res 11:458–465.
31. Melançon CE, 3rd, Liu HW (2007) Engineered biosynthesis of macrolide derivatives
bearing the non-natural deoxysugars 4-epi-D-mycaminose and 3-n-monomethylamino-
3-deoxy-D-fucose. J AmChem Soc 129:4896–4897.
32. Chan YA, Podevels AM, Kevany BM, Thomas MG (2009) Biosynthesis of polyketide
synthase extender units. Nat Prod Rep 26:90–114.
33. Eustáquio AS, et al. (2009) Biosynthesis of the salinosporamide A polyketide synthase
substrate chloroethylmalonyl-coenzyme A from S-adenosyl-L-methionine. Proc Natl
Acad Sci USA 106:12295–12300.
34. Mo S, et al. (2011) Biosynthesis of the allylmalonyl-CoA extender unit for the FK506
polyketide synthase proceeds through a dedicated polyketide synthase and facilitates
the mutasynthesis of analogues. J Am Chem Soc 133:976–985.
35. Brisson-Noel A, Trieu-Cuot P, Courvalin P (1988) Mechanism of action of spiramycin
and other macrolides. J Antimicrob Chemother 22(Suppl B):13–23.
36. Fjaervik E, Zotchev SB (2005) Biosynthesis of the polyene macrolide antibiotic nystatin
in Streptomyces noursei. Appl Microbiol Biotechnol 67:436–443.
37. Olano C, Méndez C, Salas JA (2009) Antitumor compounds from marine actinomycetes.
Mar Drugs 7:210–248.
38. Bergmann S, et al. (2007) Genomics-driven discovery of PKS-NRPS hybrid metabolites
from Aspergillus nidulans. Nat Chem Biol 3:213–217.
39. Bunet R, et al. (2008) Regulation of the synthesis of the angucyclinone antibiotic
alpomycin in Streptomyces ambofaciens by the autoregulator receptor AlpZ and its
specific ligand. J Bacteriol 190:3293–3305.
40. Gust B, Challis GL, Fowler K, Kieser T, Chater KF (2003) PCR-targeted Streptomyces
gene replacement identifies a protein domain needed for biosynthesis of the
sesquiterpene soil odor geosmin. Proc Natl Acad Sci USA 100:1541–1546.
41. Aigle B, Pang X, Decaris B, Leblond P (2005) Involvement of AlpV, a new member of
the Streptomyces antibiotic regulatory protein family, in regulation of the duplicated
type II polyketide synthase alp gene cluster in Streptomyces ambofaciens. J Bacteriol
187:2491–2500.
42. Reid R, et al. (2003) A model of structure and catalysis for ketoreductase domains in
modular polyketide synthases. Biochemistry 42:72–79.
URI: http://wrap.warwick.ac.uk/id/eprint/40407

Data sourced from Thomson Reuters' Web of Knowledge

Request changes or add full text files to a record

Actions (login required)

View Item View Item