Characterization of the Actinonin Biosynthetic Gene Cluster

Wolf F, Leipoldt F, Kulik A, Wibberg D, Kalinowski J, Kaysser L (2018)
CHEMBIOCHEM 19(11): 1189-1195.

Zeitschriftenaufsatz | Veröffentlicht | Englisch
Es wurden keine Dateien hochgeladen. Nur Publikationsnachweis!
Wolf, Felix; Leipoldt, Franziska; Kulik, Andreas; Wibberg, DanielUniBi; Kalinowski, JörnUniBi; Kaysser, Leonard
Abstract / Bemerkung
The hydroxamate moiety of the natural product actinonin mediates inhibition of metalloproteinases because of its chelating properties towards divalent cations in the active site of those enzymes. Owing to its antimicrobial activity, actinonin has served as a lead compound for the development of new antibiotic drug candidates. Recently, we identified a putative gene cluster for the biosynthesis of actinonin. Here, we confirm and characterize this cluster by heterologous pathway expression and gene-deletion experiments. We assigned the biosynthetic gene cluster to actinonin production and determine the cluster boundaries. Furthermore, we establish that ActI, an AurF-like oxygenase, is responsible for the N-hydroxylation reaction that forms the hydroxamate warhead. Our findings provide the basis for more detailed investigations of actinonin biosynthesis.
biosynthesis; heterologous expression; inhibitors; metabolism; natural; products
Page URI


Wolf F, Leipoldt F, Kulik A, Wibberg D, Kalinowski J, Kaysser L. Characterization of the Actinonin Biosynthetic Gene Cluster. CHEMBIOCHEM. 2018;19(11):1189-1195.
Wolf, F., Leipoldt, F., Kulik, A., Wibberg, D., Kalinowski, J., & Kaysser, L. (2018). Characterization of the Actinonin Biosynthetic Gene Cluster. CHEMBIOCHEM, 19(11), 1189-1195. doi:10.1002/cbic.201800116
Wolf, Felix, Leipoldt, Franziska, Kulik, Andreas, Wibberg, Daniel, Kalinowski, Jörn, and Kaysser, Leonard. 2018. “Characterization of the Actinonin Biosynthetic Gene Cluster”. CHEMBIOCHEM 19 (11): 1189-1195.
Wolf, F., Leipoldt, F., Kulik, A., Wibberg, D., Kalinowski, J., and Kaysser, L. (2018). Characterization of the Actinonin Biosynthetic Gene Cluster. CHEMBIOCHEM 19, 1189-1195.
Wolf, F., et al., 2018. Characterization of the Actinonin Biosynthetic Gene Cluster. CHEMBIOCHEM, 19(11), p 1189-1195.
F. Wolf, et al., “Characterization of the Actinonin Biosynthetic Gene Cluster”, CHEMBIOCHEM, vol. 19, 2018, pp. 1189-1195.
Wolf, F., Leipoldt, F., Kulik, A., Wibberg, D., Kalinowski, J., Kaysser, L.: Characterization of the Actinonin Biosynthetic Gene Cluster. CHEMBIOCHEM. 19, 1189-1195 (2018).
Wolf, Felix, Leipoldt, Franziska, Kulik, Andreas, Wibberg, Daniel, Kalinowski, Jörn, and Kaysser, Leonard. “Characterization of the Actinonin Biosynthetic Gene Cluster”. CHEMBIOCHEM 19.11 (2018): 1189-1195.

47 References

Daten bereitgestellt von Europe PubMed Central.

Production of actinonin, an inhibitor of aminopeptidase M, by actinomycetes.
Umezawa H, Aoyagi T, Tanaka T, Suda H, Okuyama A, Naganawa H, Hamada M, Takeuchi T., J. Antibiot. 38(11), 1985
PMID: 2867082
Actinonin: an antibiotic substance produced by an actinomycete.
GORDON JJ, KELLY BK, MILLER GA., Nature 195(), 1962
PMID: 13900478
Actinonin, a naturally occurring antibacterial agent, is a potent deformylase inhibitor.
Chen DZ, Patel DV, Hackbarth CJ, Wang W, Dreyer G, Young DC, Margolis PS, Wu C, Ni ZJ, Trias J, White RJ, Yuan Z., Biochemistry 39(6), 2000
PMID: 10684604
Human mitochondrial peptide deformylase, a new anticancer target of actinonin-based antibiotics.
Lee MD, She Y, Soskis MJ, Borella CP, Gardner JR, Hayes PA, Dy BM, Heaney ML, Philips MR, Bornmann WG, Sirotnak FM, Scheinberg DA., J. Clin. Invest. 114(8), 2004
PMID: 15489958
The crystal structures of four peptide deformylases bound to the antibiotic actinonin reveal two distinct types: a platform for the structure-based design of antibacterial agents.
Guilloteau JP, Mathieu M, Giglione C, Blanc V, Dupuy A, Chevrier M, Gil P, Famechon A, Meinnel T, Mikol V., J. Mol. Biol. 320(5), 2002
PMID: 12126617
Matlystatins, new inhibitors of type IV collagenases from Actinomadura atramentaria. III. Structure elucidation of matlystatins A to F.
Haruyama H, Ohkuma Y, Nagaki H, Ogita T, Tamaki K, Kinoshita T., J. Antibiot. 47(12), 1994
PMID: 7844042
Propioxatins A and B, new enkephalinase B inhibitors. I. Taxonomy, fermentation, isolation and biological properties.
Inaoka Y, Tamaoki H, Takahashi S, Enokita R, Okazaki T., J. Antibiot. 39(10), 1986
PMID: 3536826
YM-24074, a new peptide antibiotic. II. Structural elucidation.
Sato T, Takebayashi Y, Tokunaga T, Ozasa T., J. Antibiot. 49(8), 1996
PMID: 8823515
Safety, tolerability, and efficacy of GSK1322322 in the treatment of acute bacterial skin and skin structure infections.
Corey R, Naderer OJ, O'Riordan WD, Dumont E, Jones LS, Kurtinecz M, Zhu JZ., Antimicrob. Agents Chemother. 58(11), 2014
PMID: 25136015
Biosynthesis of the β-Lactone Proteasome Inhibitors Belactosin and Cystargolide.
Wolf F, Bauer JS, Bendel TM, Kulik A, Kalinowski J, Gross H, Kaysser L., Angew. Chem. Int. Ed. Engl. 56(23), 2017
PMID: 28452105

AUTHOR UNKNOWN, Angew. Chem. 129(), 2017
Epoxomicin and Eponemycin Biosynthesis Involves gem-Dimethylation and an Acyl-CoA Dehydrogenase-Like Enzyme.
Zettler J, Zubeil F, Kulik A, Grond S, Kaysser L., Chembiochem 17(9), 2016
PMID: 26789439
Warhead biosynthesis and the origin of structural diversity in hydroxamate metalloproteinase inhibitors.
Leipoldt F, Santos-Aberturas J, Stegmann DP, Wolf F, Kulik A, Lacret R, Popadic D, Keinhorster D, Kirchner N, Bekiesch P, Gross H, Truman AW, Kaysser L., Nat Commun 8(1), 2017
PMID: 29213087

Seemann, Bioinformatics (), 2014
GenDB--an open source genome annotation system for prokaryote genomes.
Meyer F, Goesmann A, McHardy AC, Bartels D, Bekel T, Clausen J, Kalinowski J, Linke B, Rupp O, Giegerich R, Puhler A., Nucleic Acids Res. 31(8), 2003
PMID: 12682369

Synthesis of C5-dicarboxylic acids from C2-units involving crotonyl-CoA carboxylase/reductase: the ethylmalonyl-CoA pathway.
Erb TJ, Berg IA, Brecht V, Muller M, Fuchs G, Alber BE., Proc. Natl. Acad. Sci. U.S.A. 104(25), 2007
PMID: 17548827

Biosynthesis of the salinosporamide A polyketide synthase substrate chloroethylmalonyl-coenzyme A from S-adenosyl-L-methionine.
Eustaquio AS, McGlinchey RP, Liu Y, Hazzard C, Beer LL, Florova G, Alhamadsheh MM, Lechner A, Kale AJ, Kobayashi Y, Reynolds KA, Moore BS., Proc. Natl. Acad. Sci. U.S.A. 106(30), 2009
PMID: 19590008
Biosynthesis of the allylmalonyl-CoA extender unit for the FK506 polyketide synthase proceeds through a dedicated polyketide synthase and facilitates the mutasynthesis of analogues.
Mo S, Kim DH, Lee JH, Park JW, Basnet DB, Ban YH, Yoo YJ, Chen SW, Park SR, Choi EA, Kim E, Jin YY, Lee SK, Park JY, Liu Y, Lee MO, Lee KS, Kim SJ, Kim D, Park BC, Lee SG, Kwon HJ, Suh JW, Moore BS, Lim SK, Yoon YJ., J. Am. Chem. Soc. 133(4), 2010
PMID: 21175203
Structural basis of the stereospecificity of bacterial B12-dependent 2-hydroxyisobutyryl-CoA mutase.
Kurteva-Yaneva N, Zahn M, Weichler MT, Starke R, Harms H, Muller RH, Strater N, Rohwerder T., J. Biol. Chem. 290(15), 2015
PMID: 25720495
Cloning, sequencing and characterization of the biosynthetic gene cluster of sanglifehrin A, a potent cyclophilin inhibitor.
Qu X, Jiang N, Xu F, Shao L, Tang G, Wilkinson B, Liu W., Mol Biosyst 7(3), 2011
PMID: 21416665

Characterization of the N-oxygenase AurF from Streptomyces thioletus.
Chanco E, Choi YS, Sun N, Vu M, Zhao H., Bioorg. Med. Chem. 22(20), 2014
PMID: 24973817

Kieser, 2000

Sambrook, 2001
antiSMASH: rapid identification, annotation and analysis of secondary metabolite biosynthesis gene clusters in bacterial and fungal genome sequences.
Medema MH, Blin K, Cimermancic P, de Jager V, Zakrzewski P, Fischbach MA, Weber T, Takano E, Breitling R., Nucleic Acids Res. 39(Web Server issue), 2011
PMID: 21672958
Gapped BLAST and PSI-BLAST: a new generation of protein database search programs.
Altschul SF, Madden TL, Schaffer AA, Zhang J, Zhang Z, Miller W, Lipman DJ., Nucleic Acids Res. 25(17), 1997
PMID: 9254694
NRPSpredictor2--a web server for predicting NRPS adenylation domain specificity.
Rottig M, Medema MH, Blin K, Weber T, Rausch C, Kohlbacher O., Nucleic Acids Res. 39(Web Server issue), 2011
PMID: 21558170
Minimum Information about a Biosynthetic Gene cluster.
Medema MH, Kottmann R, Yilmaz P, Cummings M, Biggins JB, Blin K, de Bruijn I, Chooi YH, Claesen J, Coates RC, Cruz-Morales P, Duddela S, Dusterhus S, Edwards DJ, Fewer DP, Garg N, Geiger C, Gomez-Escribano JP, Greule A, Hadjithomas M, Haines AS, Helfrich EJ, Hillwig ML, Ishida K, Jones AC, Jones CS, Jungmann K, Kegler C, Kim HU, Kotter P, Krug D, Masschelein J, Melnik AV, Mantovani SM, Monroe EA, Moore M, Moss N, Nutzmann HW, Pan G, Pati A, Petras D, Reen FJ, Rosconi F, Rui Z, Tian Z, Tobias NJ, Tsunematsu Y, Wiemann P, Wyckoff E, Yan X, Yim G, Yu F, Xie Y, Aigle B, Apel AK, Balibar CJ, Balskus EP, Barona-Gomez F, Bechthold A, Bode HB, Borriss R, Brady SF, Brakhage AA, Caffrey P, Cheng YQ, Clardy J, Cox RJ, De Mot R, Donadio S, Donia MS, van der Donk WA, Dorrestein PC, Doyle S, Driessen AJ, Ehling-Schulz M, Entian KD, Fischbach MA, Gerwick L, Gerwick WH, Gross H, Gust B, Hertweck C, Hofte M, Jensen SE, Ju J, Katz L, Kaysser L, Klassen JL, Keller NP, Kormanec J, Kuipers OP, Kuzuyama T, Kyrpides NC, Kwon HJ, Lautru S, Lavigne R, Lee CY, Linquan B, Liu X, Liu W, Luzhetskyy A, Mahmud T, Mast Y, Mendez C, Metsa-Ketela M, Micklefield J, Mitchell DA, Moore BS, Moreira LM, Muller R, Neilan BA, Nett M, Nielsen J, O'Gara F, Oikawa H, Osbourn A, Osburne MS, Ostash B, Payne SM, Pernodet JL, Petricek M, Piel J, Ploux O, Raaijmakers JM, Salas JA, Schmitt EK, Scott B, Seipke RF, Shen B, Sherman DH, Sivonen K, Smanski MJ, Sosio M, Stegmann E, Sussmuth RD, Tahlan K, Thomas CM, Tang Y, Truman AW, Viaud M, Walton JD, Walsh CT, Weber T, van Wezel GP, Wilkinson B, Willey JM, Wohlleben W, Wright GD, Ziemert N, Zhang C, Zotchev SB, Breitling R, Takano E, Glockner FO., Nat. Chem. Biol. 11(9), 2015
PMID: 26284661
Merochlorins A-D, cyclic meroterpenoid antibiotics biosynthesized in divergent pathways with vanadium-dependent chloroperoxidases.
Kaysser L, Bernhardt P, Nam SJ, Loesgen S, Ruby JG, Skewes-Cox P, Jensen PR, Fenical W, Moore BS., J. Am. Chem. Soc. 134(29), 2012
PMID: 22784372
Genetic basis for the biosynthesis of the pharmaceutically important class of epoxyketone proteasome inhibitors.
Schorn M, Zettler J, Noel JP, Dorrestein PC, Moore BS, Kaysser L., ACS Chem. Biol. 9(1), 2013
PMID: 24168704
One-step inactivation of chromosomal genes in Escherichia coli K-12 using PCR products.
Datsenko KA, Wanner BL., Proc. Natl. Acad. Sci. U.S.A. 97(12), 2000
PMID: 10829079
Analysis of Streptomyces avermitilis genes required for avermectin biosynthesis utilizing a novel integration vector.
MacNeil DJ, Gewain KM, Ruby CL, Dezeny G, Gibbons PH, MacNeil T., Gene 111(1), 1992
PMID: 1547955
PCR-targeted Streptomyces gene replacement identifies a protein domain needed for biosynthesis of the sesquiterpene soil odor geosmin.
Gust B, Challis GL, Fowler K, Kieser T, Chater KF., Proc. Natl. Acad. Sci. U.S.A. 100(4), 2003
PMID: 12563033

Markieren/ Markierung löschen
Markierte Publikationen

Open Data PUB

Web of Science

Dieser Datensatz im Web of Science®

PMID: 29600569
PubMed | Europe PMC

Suchen in

Google Scholar