Zusammenfassung:
Nicht-ribosomal synthetisierte Peptide weisen eine hohe strukturelle Vielfalt auf, die durch die Anwesenheit vieler nicht-proteinogener Bausteine hervorgerufen wird. Es wurde gezeigt, dass diese Bausteine oft essentiell für die Bioaktivität des jeweiligen Naturstoffs sind, jedoch ist die Biosynthese vieler dieser Bausteine weitestgehend nicht verstanden. Die hier vorgestellte Arbeit beschäftigt sich mit drei chemisch anspruchsvollen Modifikations-reaktionen an freien Aminosäuren, die effektiv durch so genannte Modifikationsenzyme durchgeführt werden. Die ungewöhnlichen, modifizierten Aminosäuren dienen dann als Synthesebausteine für die nicht-ribosomale Peptidsynthese.
Im ersten Teil der Arbeit wird der Biosyntheseweg von Nδ-hydroxylierten und Nδ formylierten Ornithin-Resten in vitro untersucht. Diese Bausteine werden für die Biosynthese des Tris-Hydroxamat-Siderophors Coelichelin benötigt, in dem sie für die Komplexierung von Eisen(III)-Ionen verantwortlich sind. Für die Untersuchungen wurden die Flavin-abhängige Monooxygenase CchB und die Formyltransferase CchA aus Streptomyces coelicolor rekombinant hergestellt und biochemisch charakterisiert. Für CchB konnte, im Gegensatz zu CchA, Aktivität in vitro nachgewiesen werden. Da das Enzym ausschließlich freies L-Ornithin hydroxylierte, konnte gezeigt werden, dass diese Hydroxylierungsreaktion den ersten Schritt in der Biosynthese von Coelichelin darstellt und somit essentiell für dessen Produktion ist.
Der zweite Teil der Arbeit beschäftigt sich mit der stereospezifischen Cβ-Hydroxylierung von L Arginin, die von einem organisch-synthetischen Standpunkt aus betrachtet sehr aufwendig ist. Diese Reaktion wird von der nicht-Häm Eisen(II)- und α-Ketoglutarat-abhängigen Mono-oxygenase VioC aus Streptomyces vinaceus katalysiert und resultiert in dem Baustein erythro-β-Hydroxy-Arginin. Dieser wird nach einer weiteren Modifikationsreaktion in das Peptidgerüst des Antibiotikums Viomycin eingebaut. Interessanterweise katalysiert der Großteil von nicht-Häm Eisen(II)-/α-Ketoglutarat-abhängigen Monooxygenasen die Bildung von threo Diastereomeren. Neben der biochemischen Charakterisierung von VioC wurde in dieser Arbeit auch die Lösung der Kristallstruktur der Monooxygenase durchgeführt. Anhand der erhaltenen Daten konnten die unerwartete Substrattoleranz von VioC und die für diese Enzymklasse ungewöhnliche erythro Stereochemie erklärt werden.
Eine weitere Cβ-Funktionalisierung einer freien Aminosäure wird im dritten Teil dieser Arbeit untersucht. Der nicht-proteinogene Vorläuferbaustein (2S,3S)-β-Methyl-Phenylalanin, dessen chemische Synthese sehr anspruchsvoll ist, wird in das Glykopeptid-Antibiotikum Mannopeptimycin in Streptomyces hygroscopicus eingebaut. Um den Biosyntheseweg zu untersuchen, wurde die S-Adenosylmethionin-abhängige Methyltransferase MppJ in vitro auf Aktivität getestet. Es konnte gezeigt werden, dass nicht wie erwartet Phenylalanin direkt methyliert wird, sondern dass die α-Ketosäure Phenylpyruvat von MppJ zu β-Methyl-Phenylpyruvat konvertiert wird. Eine anschließende Transaminierungsreaktion mit der Pyridoxal-5’-Phosphat-abhängigen Aminotransferase IlvE aus dem Primärmetabolismus von Streptomyces coelicolor resultierte in der Bildung der beiden Diastereomere (2S,3S)- und (2S,3R)-β-Methyl-Phenylalanin. Es konnte nicht endgültig gezeigt werden, ob die MppJ-katalysierte Methylierungsreaktion stereospezifisch verläuft oder nicht. Allerdings wurden in dieser Arbeit neue Erkenntnisse bezüglich der Cβ-Funktionalisierung von Phenylalanin bzw. Phenylpyruvat erhalten.
Bibliographie / References
- Laemmli, U. K. Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature 1970, 227, 680-685.
- Tanovic, A., Samel, S. A., Essen, L. O. and Marahiel, M. A. Crystal structure of the termination module of a nonribosomal peptide synthetase. Science 2008, 321, 659-663. [41]
- Heinzelmann, E., Berger, S., Puk, O., Reichenstein, B., Wohlleben, W. and Schwartz, D. A glutamate mutase is involved in the biosynthesis of the lipopeptide antibiotic friulimicin in Actinoplanes friuliensis. Antimicrob Agents Chemother 2003, 47, 447-457.
- Yeh, E., Kohli, R. M., Bruner, S. D. and Walsh, C. T. Type II thioesterase restores activity of a NRPS module stalled with an aminoacyl-S-enzyme that cannot be elongated. Chembiochem 2004, 5, 1290- 1293. [28]
- Stein, D. B., Linne, U., Hahn, M. and Marahiel, M. A. Impact of epimerization domains on the intermodular transfer of enzyme-bound intermediates in nonribosomal peptide synthesis. Chembiochem 2006, 7, 1807-1814. [46]
- Schwarzer, D., Finking, R. and Marahiel, M. A. Nonribosomal peptides: From genes to products. Nat Prod Rep 2003, 20, 275-287.
- Buchenau, B. and Thauer, R. K. Tetrahydrofolate-specific enzymes in Methanosarcina barkeri and growth dependence of this methanogenic archaeon on folic acid or p-aminobenzoic acid. Arch Microbiol 2004, 182, 313-325.
- Bennett, J. and Scott, K. J. Quantitative staining of fraction I protein in polyacrylamide gels using coomassie brillant blue. Anal Biochem 1971, 43, 173-182.
- Clifton, I. J., McDonough, M. A., Ehrismann, D., Kershaw, N. J., Granatino, N. and Schofield, C. J. Structural studies on 2-oxoglutarate oxygenases and related double-stranded β-helix fold proteins. J Inorg Biochem 2006, 100, 644-669.
- Schofield, C. J. and Zhang, Z. Structural and mechanistic studies on 2-oxoglutarate-dependent oxygenases and related enzymes. Curr Opin Struct Biol 1999, 9, 722-731.
- Kershaw, N. J., Caines, M. E., Sleeman, M. C. and Schofield, C. J. The enzymology of clavam and carbapenem biosynthesis. Chem Commun (Camb) 2005, 4251-4263.
- [97] Bruijnincx, P. C., van Koten, G. and Klein Gebbink, R. J. Mononuclear non-heme iron enzymes with the 2-His-1-carboxylate facial triad: Recent developments in enzymology and modeling studies. Chem Soc Rev 2008, 37, 2716-2744. [98]
- Fauci, A. S. Multidrug-resistant and extensively drug-resistant tuberculosis: The national institute of allergy and infectious diseases research agenda and recommendations for priority research. J Infect Dis 2008, 197, 1493-1498.
- Sofia, H. J., Chen, G., Hetzler, B. G., Reyes-Spindola, J. F. and Miller, N. E. Radical SAM, a novel protein superfamily linking unresolved steps in familiar biosynthetic pathways with radical mechanisms: Functional characterization using new analysis and information visualization methods. Nucleic Acids Res 2001, 29, 1097-1106.
- Caboche, S., Pupin, M., Leclere, V., Fontaine, A., Jacques, P. and Kucherov, G. Norine: A database of nonribosomal peptides. Nucleic Acids Res 2008, 36, D326-331. [14]
- Bruner, S. D., Weber, T., Kohli, R. M., Schwarzer, D., Marahiel, M. A., Walsh, C. T. and Stubbs, M. T. Structural basis for the cyclization of the lipopeptide antibiotic surfactin by the thioesterase domain SrfTE. Structure 2002, 10, 301-310. [37]
- Jensen, S. E. and Paradkar, A. S. Biosynthesis and molecular genetics of clavulanic acid. Antonie Van Leeuwenhoek 1999, 75, 125-133.
- Wu, J. C. and Santi, D. V. Kinetic and catalytic mechanism of HhaI methyltransferase. J Biol Chem 1987, 262, 4778-4786.
- Schenk, G., Pau, M. Y. and Solomon, E. I. Comparison between the geometric and electronic structures and reactivities of [FeNO]7 and [FeO2]8 complexes: A density functional theory study. J Am Chem Soc 2004, 126, 505-515.
- Johansen, S. K., Maus, C. E., Plikaytis, B. B. and Douthwaite, S. Capreomycin binds across the ribosomal subunit interface using TlyA-encoded 2'-O-methylations in 16S and 23S rRNAs. Mol Cell 2006, 23, 173-182.
- Wierenga, R. K., Terpstra, P. and Hol, W. G. Prediction of the occurrence of the ADP-binding βαβ-fold in proteins, using an amino acid sequence fingerprint. J Mol Biol 1986, 187, 101-107. [84]
- Muller, I., Kahnert, A., Pape, T., Sheldrick, G. M., Meyer-Klaucke, W., Dierks, T., Kertesz, M. and Uson, I. Crystal structure of the alkylsulfatase AtsK: Insights into the catalytic mechanism of the Fe(II) α-ketoglutarate-dependent dioxygenase superfamily. Biochemistry 2004, 43, 3075-3088.
- Guenzi, E., Galli, G., Grgurina, I., Gross, D. C. and Grandi, G. Characterization of the syringomycin synthetase gene cluster. A link between prokaryotic and eukaryotic peptide synthetases. J Biol Chem 1998, 273, 32857-32863.
- Kabsch, W. Automatic processing of rotation diffraction data from crystals of initially unknown symmetry and cell constants. J. Appl. Cryst. 1993, 26, 795-800.
- Martinkus, K. J., Tann, C. H. and Gould, S. J. The biosynthesis of the streptolidine moiety in streptothricin f. Tetrahedron 1983, 39, 3493-3505.
- Legrain, C. and Stalon, V. Ornithine carbamoyltransferase from Escherichia coli W. Purification, structure and steady-state kinetic analysis. Eur J Biochem 1976, 63, 289-301.
- Bull, S. D., Davies, S. G., Epstein, S. W., Garner, A. C., Mujtaba, N., Roberts, P. M., Savory, E. D., Smith, A. D., Tamayo, J. A. and Watkin, D. J. Enantiodiscrimination of racemic electrophiles by diketopiperazine enolates: Asymmetric synthesis of methyl 2-amino-3-aryl-butanoates and 3-methyl- aspartates. Tetrahedron 2006, 62, 7911-7925.
- Pohlmann, V. and Marahiel, M. A. δ-amino group hydroxylation of L-ornithine during coelichelin biosynthesis. Org Biomol Chem 2008, 6, 1843-1848.
- Lambalot, R. H., Gehring, A. M., Flugel, R. S., Zuber, P., LaCelle, M., Marahiel, M. A., Reid, R., Khosla, C. and Walsh, C. T. A new enzyme superfamily -the phosphopantetheinyl transferases. Chem Biol 1996, 3, 923-936.
- Du, L., Chen, M., Sanchez, C. and Shen, B. An oxidation domain in the BlmIII non-ribosomal peptide synthetase probably catalyzing thiazole formation in the biosynthesis of the anti-tumor drug bleomycin in Streptomyces verticillus ATCC15003. FEMS Microbiol Lett 2000, 189, 171-175. [55]
- Fischbach, M. A. and Walsh, C. T. Antibiotics for emerging pathogens. Science 2009, 325, 1089-1093.
- Sitaram, N. Antimicrobial peptides with unusual amino acid compositions and unusual structures. Curr Med Chem 2006, 13, 679-696.
- Davis, F. A., Lee, S., Zhang, H. and Fanelli, D. L. Applications of the sulfinimine-mediated asymmetric strecker synthesis to the synthesis of α-alkyl α-amino acids. J Org Chem 2000, 65, 8704-8708.
- Bradford, M. M. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 1976, 72, 248-254.
- Davis, F. A., Portonovo, P. S., Reddy, R. E. and Chiu Yh, Y. Asymmetric strecker synthesis using enantiopure sulfinimines and diethylaluminium cyanide: The alcohol effect. J Org Chem 1996, 61, 440- 441.
- Roff, G. J., Lloyd, R. C. and Turner, N. J. A versatile chemo-enzymatic route to enantiomerically pure β-branched α-amino acids. Journal of the American Chemical Society 2004, 126, 4098-4099.
- Davis, F. A., Liu, H., Zhou, P., Fang, T., Reddy, G. V. and Zhang, Y. Aza-darzens asymmetric synthesis of N-(p-toluenesulfinyl)aziridine 2-carboxylate esters from sulfinimines (N-sulfinyl imines). The Journal of Organic Chemistry 1999, 64, 7559-7567.
- Lipmann, F. Bacterial production of antibiotic polypeptides by thiol-linked synthesis on protein templates. Adv Microb Physiol 1980, 21, 227-266. [15] Schwarzer, D. and Marahiel, M. A. Multimodular biocatalysts for natural product assembly. Naturwissenschaften 2001, 88, 93-101. [16]
- Cantoni, G. L. Biological methylation: Selected aspects. Annu Rev Biochem 1975, 44, 435-451.
- Hatano, K., Nogami, I., Higashide, E. and Kishi, T. Biosynthesis of enduracidin: Origin of enduracididine and other amino acids. Agric Biol Chem 1984, 48, 1503-1508.
- Rachid, S., Krug, D., Weissman, K. J. and Muller, R. Biosynthesis of (R)-β-tyrosine and its incorporation into the highly cytotoxic chondramides produced by Chondromyces crocatus. J Biol Chem 2007, 282, 21810-21817.
- Milne, C., Powell, A., Jim, J., Al Nakeeb, M., Smith, C. P. and Micklefield, J. Biosynthesis of the (2S,3R)-3-methyl glutamate residue of nonribosomal lipopeptides. J Am Chem Soc 2006, 128, 11250- 11259.
- Kagamiyama, H. and Hayashi, H. Branched-chain amino-acid aminotransferase of Escherichia coli. Methods Enzymol 2000, 324, 103-113.
- Gill, S. C. and von Hippel, P. H. Calculation of protein extinction coefficients from amino acid sequence data. Anal Biochem 1989, 182, 319-326.
- Harle, J. and Bechthold, A. Chapter 12. The power of glycosyltransferases to generate bioactive natural compounds. Methods Enzymol 2009, 458, 309-333. [68]
- Ackerley, D. F. and Lamont, I. L. Characterization and genetic manipulation of peptide synthetases in Pseudomonas aeruginosa PAO1 in order to generate novel pyoverdines. Chem Biol 2004, 11, 971-980.
- Quadri, L. E., Weinreb, P. H., Lei, M., Nakano, M. M., Zuber, P. and Walsh, C. T. Characterization of Sfp, a Bacillus subtilis phosphopantetheinyl transferase for peptidyl carrier protein domains in peptide synthetases. Biochemistry 1998, 37, 1585-1595. [25]
- Magarvey, N. A., Ehling-Schulz, M. and Walsh, C. T. Characterization of the cereulide NRPS α-hydroxy acid specifying modules: Activation of α-keto acids and chiral reduction on the assembly line. J Am Chem Soc 2006, 128, 10698-10699.
- Clugston, S. L., Sieber, S. A., Marahiel, M. A. and Walsh, C. T. Chirality of peptide bond-forming condensation domains in nonribosomal peptide synthetases: The C5 domain of tyrocidine synthetase is a (D)C(L) catalyst. Biochemistry 2003, 42, 12095-12104. [34]
- Yeh, E., Blasiak, L. C., Koglin, A., Drennan, C. L. and Walsh, C. T. Chlorination by a long-lived intermediate in the mechanism of flavin-dependent halogenases. Biochemistry 2007, 46, 1284-1292.
- Westrich, L., Heide, L. and Li, S. M. CloN6, a novel methyltransferase catalysing the methylation of the pyrrole-2-carboxyl moiety of clorobiocin. Chembiochem 2003, 4, 768-773.
- Fujimori, D. G., Hrvatin, S., Neumann, C. S., Strieker, M., Marahiel, M. A. and Walsh, C. T. Cloning and characterization of the biosynthetic gene cluster for kutznerides. Proc Natl Acad Sci U S A 2007, 104, 16498-16503.
- Lovell, C. R., Przybyla, A. and Ljungdahl, L. G. Cloning and expression in Escherichia coli of the Clostridium thermoaceticum gene encoding thermostable formyltetrahydrofolate synthetase. Arch Microbiol 1988, 149, 280-285.
- Visca, P., Ciervo, A. and Orsi, N. Cloning and nucleotide sequence of the PvdA gene encoding the pyoverdin biosynthetic enzyme L-ornithine N5-oxygenase in Pseudomonas aeruginosa. J Bacteriol 1994, 176, 1128-1140.
- Challis, G. L. and Ravel, J. Coelichelin, a new peptide siderophore encoded by the Streptomyces coelicolor genome: Structure prediction from the sequence of its non-ribosomal peptide synthetase. FEMS Microbiol Lett 2000, 187, 111-114.
- Collaborative Computing Project Number 4. The CCP4 suite: Programs for protein crystallography. Acta Crystallogr D Biol Crystallogr 1994, 50, 760-763.
- Koglin, A., Mofid, M. R., Lohr, F., Schafer, B., Rogov, V. V., Blum, M. M., Mittag, T., Marahiel, M. A., Bernhard, F. and Dotsch, V. Conformational switches modulate protein interactions in peptide antibiotic synthetases. Science 2006, 312, 273-276. [30] Bergendahl, V., Linne, U. and Marahiel, M. A. Mutational analysis of the C-domain in nonribosomal peptide synthesis. Eur J Biochem 2002, 269, 620-629. [31] Stachelhaus, T., Mootz, H. D., Bergendahl, V. and Marahiel, M. A. Peptide bond formation in nonribosomal peptide biosynthesis. Catalytic role of the condensation domain. J Biol Chem 1998, 273, 22773-22781. [32] Belshaw, P. J., Walsh, C. T. and Stachelhaus, T. Aminoacyl-CoAs as probes of condensation domain selectivity in nonribosomal peptide synthesis. Science 1999, 284, 486-489. [33]
- Dye, C., Scheele, S., Dolin, P., Pathania, V. and Raviglione, M. C. Consensus statement. Global burden of tuberculosis: Estimated incidence, prevalence, and mortality by country. Who global surveillance and monitoring project. Jama 1999, 282, 677-686.
- Ju, J., Ozanick, S. G., Shen, B. and Thomas, M. G. Conversion of (2S)-arginine to (2S,3R)- capreomycidine by VioC and VioD from the viomycin biosynthetic pathway of Streptomyces sp. Strain ATCC11861. Chembiochem 2004, 5, 1281-1285.
- Chen, H. and Walsh, C. T. Coumarin formation in novobiocin biosynthesis: β-hydroxylation of the aminoacyl enzyme tyrosyl-S-NovH by a cytochrome P450 NovI. Chem Biol 2001, 8, 301-312.
- Pacholec, M., Tao, J. and Walsh, C. T. CouO and NovO: C-methyltransferases for tailoring the aminocoumarin scaffold in coumermycin and novobiocin antibiotic biosynthesis. Biochemistry 2005, 44, 14969-14976.
- Hosokawa, K. and Stanier, R. Y. Crystallization and properties of p-hydroxybenzoate hydroxylase from Pseudomonas putida. J Biol Chem 1966, 241, 2453-2460.
- Malito, E., Alfieri, A., Fraaije, M. W. and Mattevi, A. Crystal structure of a baeyer-villiger monooxygenase. Proc Natl Acad Sci U S A 2004, 101, 13157-13162. [86]
- Clifton, I. J., Doan, L. X., Sleeman, M. C., Topf, M., Suzuki, H., Wilmouth, R. C. and Schofield, C. J. Crystal structure of carbapenem synthase (CarC). J Biol Chem 2003, 278, 20843-20850.
- Cheng, X., Kumar, S., Posfai, J., Pflugrath, J. W. and Roberts, R. J. Crystal structure of the HhaI DNA methyltransferase complexed with S-adenosyl-L-methionine. Cell 1993, 74, 299-307.
- Blasiak, L. C., Vaillancourt, F. H., Walsh, C. T. and Drennan, C. L. Crystal structure of the non-haem iron halogenase SyrB2 in Syringomycin biosynthesis. Nature 2006, 440, 368-371.
- Greenhagen, B. T., Shi, K., Robinson, H., Gamage, S., Bera, A. K., Ladner, J. E. and Parsons, J. F. Crystal structure of the pyocyanin biosynthetic protein PhzS. Biochemistry 2008, 47, 5281-5289.
- Reuter, K., Mofid, M. R., Marahiel, M. A. and Ficner, R. Crystal structure of the surfactin synthetase- activating enzyme Sfp: A prototype of the 4'-phosphopantetheinyl transferase superfamily. Embo J 1999, 18, 6823-6831.
- Goto, M., Miyahara, I., Hayashi, H., Kagamiyama, H. and Hirotsu, K. Crystal structures of branched- chain amino acid aminotransferase complexed with glutamate and glutarate: True reaction intermediate and double substrate recognition of the enzyme. Biochemistry 2003, 42, 3725-3733.
- Yu, B., Edstrom, W. C., Benach, J., Hamuro, Y., Weber, P. C., Gibney, B. R. and Hunt, J. F. Crystal structures of catalytic complexes of the oxidative DNA/RNA repair enzyme AlkB. Nature 2006, 439, 879-884.
- Bernhardt, R. Cytochromes P450 as versatile biocatalysts. J Biotechnol 2006, 124, 128-145.
- Miao, V., Coeffet-Legal, M. F., Brian, P., Brost, R., Penn, J., Whiting, A., Martin, S., Ford, R., Parr, I., Bouchard, M., Silva, C. J., Wrigley, S. K. and Baltz, R. H. Daptomycin biosynthesis in Streptomyces roseosporus: Cloning and analysis of the gene cluster and revision of peptide stereochemistry. Microbiology 2005, 151, 1507-1523. [58]
- Stirk, H. J., Woolfson, D. N., Hutchinson, E. G. and Thornton, J. M. Depicting topology and handedness in jellyroll structures. FEBS Lett 1992, 308, 1-3.
- Yang, X. and Ma, K. Determination of hydrogen peroxide generated by reduced nicotinamide adenine dinucleotide oxidase. Anal Biochem 2005, 344, 130-134.
- Costas, M., Mehn, M. P., Jensen, M. P. and Que, L., Jr. Dioxygen activation at mononuclear nonheme iron active sites: Enzymes, models, and intermediates. Chem Rev 2004, 104, 939-986. [99] Vaillancourt, F. H., Bolin, J. T. and Eltis, L. D. The ins and outs of ring-cleaving dioxygenases. Crit Rev Biochem Mol Biol 2006, 41, 241-267.
- Schrettl, M., Bignell, E., Kragl, C., Sabiha, Y., Loss, O., Eisendle, M., Wallner, A., Arst, H. N., Jr., Haynes, K. and Haas, H. Distinct roles for intra-and extracellular siderophores during Aspergillus fumigatus infection. PLoS Pathog 2007, 3, 1195-1207.
- Liou, Y. F. and Tanaka, N. Dual actions of viomycin on the ribosomal functions. Biochem Biophys Res Commun 1976, 71, 477-483.
- Chen, H., O'Connor, S., Cane, D. E. and Walsh, C. T. Epothilone biosynthesis: Assembly of the methylthiazolylcarboxy starter unit on the EpoB subunit. Chem Biol 2001, 8, 899-912.
- Reimmann, C., Patel, H. M., Serino, L., Barone, M., Walsh, C. T. and Haas, D. Essential PchG- dependent reduction in pyochelin biosynthesis of Pseudomonas aeruginosa. J Bacteriol 2001, 183, 813- 820. [56]
- Price, J. C., Barr, E. W., Glass, T. E., Krebs, C. and Bollinger, J. M., Jr. Evidence for hydrogen abstraction from C1 of taurine by the high-spin Fe(IV) intermediate detected during oxygen activation by taurine: α-ketoglutarate dioxygenase (TauD). J Am Chem Soc 2003, 125, 13008-13009.
- Riggs-Gelasco, P. J., Price, J. C., Guyer, R. B., Brehm, J. H., Barr, E. W., Bollinger, J. M., Jr. and Krebs, C. EXAFS spectroscopic evidence for an Fe=O unit in the Fe(IV) intermediate observed during oxygen activation by taurine: α-ketoglutarate dioxygenase. J Am Chem Soc 2004, 126, 8108-8109.
- Li, G., Patel, D. and Hruby, V. J. Exploration for large-scale stereoselective synthesis of unusual amino acids by using 4-phenyloxazolidin-2-one as a new chiral resolution reagent. J. Chem. Soc., Perkin Trans. 1 1994, 3057 -3059.
- Macheroux, P., Plattner, H. J., Romaguera, A. and Diekmann, H. FAD and substrate analogs as probes for lysine N6-hydroxylase from Escherichia coli EN 222. Eur J Biochem 1993, 213, 995-1002.
- Yeh, E., Cole, L. J., Barr, E. W., Bollinger, J. M., Jr., Ballou, D. P. and Walsh, C. T. Flavin redox chemistry precedes substrate chlorination during the reaction of the flavin-dependent halogenase RebH. Biochemistry 2006, 45, 7904-7912. [89]
- Moonen, M. J. H., Fraaije, M. W., Rietjens, Y. M. C. M., Laane, C. and van Berkel, W. J. H. Flavoenzyme-catalyzed oxygenations and oxidations of phenolic compounds. Adv Synth Catal 2002, 344, 1-13. [80] Entsch, B. and Ballou, D. P. Purification, properties, and oxygen reactivity of p-hydroxybenzoate hydroxylase from Pseudomonas aeruginosa. Biochim Biophys Acta 1989, 999, 313-322. [81] Entsch, B. and van Berkel, W. J. Structure and mechanism of para-hydroxybenzoate hydroxylase. Faseb J 1995, 9, 476-483. [82] Entsch, B., Cole, L. J. and Ballou, D. P. Protein dynamics and electrostatics in the function of p-hydroxybenzoate hydroxylase. Arch Biochem Biophys 2005, 433, 297-311. [83]
- Chen, H., Hubbard, B. K., O'Connor, S. E. and Walsh, C. T. Formation of β-hydroxy histidine in the biosynthesis of nikkomycin antibiotics. Chem Biol 2002, 9, 103-112.
- Yin, X., McPhail, K. L., Kim, K. J. and Zabriskie, T. M. Formation of the nonproteinogenic amino acid 2S,3R-capreomycidine by VioD from the viomycin biosynthesis pathway. Chembiochem 2004, 5, 1278- 1281.
- Rabinowitz, J. C. and Pricer, W. E., Jr. Formyltetrahydrofolate synthetase. I. Isolation and crystallization of the enzyme. J Biol Chem 1962, 237, 2898-2902.
- Kopp, F., Linne, U., Oberthur, M. and Marahiel, M. A. Harnessing the chemical activation inherent to carrier protein-bound thioesters for the characterization of lipopeptide fatty acid tailoring enzymes. J Am Chem Soc 2008, 130, 2656-2666. [79]
- Sono, M., Roach, M. P., Coulter, E. D. and Dawson, J. H. Heme-containing oxygenases. Chem Rev 1996, 96, 2841-2888.
- Ge, L. and Seah, S. Y. Heterologous expression, purification, and characterization of an L-ornithine N(5)-hydroxylase involved in pyoverdine siderophore biosynthesis in Pseudomonas aeruginosa.
- Li, B. F., Yuan, K., Zhang, M. J., Wu, H., Dai, L. X., Wang, Q. R. and Hou, X. L. Highly diastereoselective strecker reaction of enolizable aliphatic sulfinimines. J Org Chem 2003, 68, 6264- 6267.
- Konz, D. and Marahiel, M. A. How do peptide synthetases generate structural diversity? Chem Biol 1999, 6, R39-48. [42] Stachelhaus, T. and Walsh, C. T. Mutational analysis of the epimerization domain in the initiation module pheate of gramicidin s synthetase. Biochemistry 2000, 39, 5775-5787. [43]
- Singh, G. M., Fortin, P. D., Koglin, A. and Walsh, C. T. β-hydroxylation of the aspartyl residue in the phytotoxin syringomycin E: Characterization of two candidate hydroxylases AspH and SyrP in Pseudomonas syringae. Biochemistry 2008, 47, 11310-11320. [72] Meneely, K. M. and Lamb, A. L. Biochemical characterization of a flavin adenine dinculeotide- dependent monooxygenase, ornithine hydroxylase from Pseudomonas aeruginosa, suggests a novel reaction mechanism. Biochemistry 2007, 46, 11930-11937. [73]
- Cotton, J. L., Tao, J. and Balibar, C. J. Identification and characterization of the Staphylococcus aureus gene cluster coding for staphyloferrin A. Biochemistry 2009, 48, 1025-1035.
- Yin, X., O'Hare, T., Gould, S. J. and Zabriskie, T. M. Identification and cloning of genes encoding viomycin biosynthesis from Streptomyces vinaceus and evidence for involvement of a rare oxygenase. Gene 2003, 312, 215-224.
- Fiss, E. H., Yu, S. and Jacobs Jr, W. R. Identification of genes involved in the sequestration of iron in mycobacteria: The ferric exochelin biosynthetic and uptake pathways. Mol Microbiol 1994, 14, 557- 569.
- Felnagle, E. A., Rondon, M. R., Berti, A. D., Crosby, H. A. and Thomas, M. G. Identification of the biosynthetic gene cluster and an additional gene for resistance to the antituberculosis drug capreomycin. Appl Environ Microbiol 2007, 73, 4162-4170. [65] Wilkinson, B. and Micklefield, J. Chapter 14. Biosynthesis of nonribosomal peptide precursors. Methods Enzymol 2009, 458, 353-378. [66]
- Hager, L. P., Morris, D. R., Brown, F. S. and Eberwein, H. Chloroperoxidase. II. Utilization of halogen anions. J Biol Chem 1966, 241, 1769-1777.
- Laursen, B. S., Sorensen, H. P., Mortensen, K. K. and Sperling-Petersen, H. U. Initiation of protein synthesis in bacteria. Microbiol Mol Biol Rev 2005, 69, 101-123. [51] Rouhiainen, L., Paulin, L., Suomalainen, S., Hyytiainen, H., Buikema, W., Haselkorn, R. and Sivonen, K. Genes encoding synthetases of cyclic depsipeptides, anabaenopeptilides, in Anabaena strain 90. Mol Microbiol 2000, 37, 156-167. [52] Schoenafinger, G., Schracke, N., Linne, U. and Marahiel, M. A. Formylation domain: An essential modifying enzyme for the nonribosomal biosynthesis of linear gramicidin. J Am Chem Soc 2006, 128, 7406-7407. [53] Miller, D. A., Walsh, C. T. and Luo, L. C-methyltransferase and cyclization domain activity at the intraprotein PK/NRP switch point of yersiniabactin synthetase. J Am Chem Soc 2001, 123, 8434-8435. [54]
- Haltli, B., Tan, Y., Magarvey, N. A., Wagenaar, M., Yin, X., Greenstein, M., Hucul, J. A. and Zabriskie, T. M. Investigating β-hydroxyenduracididine formation in the biosynthesis of the mannopeptimycins. Chem Biol 2005, 12, 1163-1168.
- Huang, Y. T., Lyu, S. Y., Chuang, P. H., Hsu, N. S., Li, Y. S., Chan, H. C., Huang, C. J., Liu, Y. C., Wu, C. J., Yang, W. B. and Li, T. L. In vitro characterization of enzymes involved in the synthesis of nonproteinogenic residue (2S,3S)-β-methylphenylalanine in glycopeptide antibiotic mannopeptimycin. Chembiochem 2009, 10, 2480-2487.
- McMorran, B. J., Kumara, H. M., Sullivan, K. and Lamont, I. L. Involvement of a transformylase enzyme in siderophore synthesis in Pseudomonas aeruginosa. Microbiology 2001, 147, 1517-1524. [74] van Berkel, W. J., Kamerbeek, N. M. and Fraaije, M. W. Flavoprotein monooxygenases, a diverse class of oxidative biocatalysts. J Biotechnol 2006, 124, 670-689. [75]
- Speedie, M. K., Hornemann, U. and Floss, H. G. Isolation and characterization of tryptophan transaminase and indolepyruvate C-methyltransferase. Enzymes involved in indolmycin biosynthesis in Streptomyces griseus. J Biol Chem 1975, 250, 7819-7825.
- Price, J. C., Barr, E. W., Hoffart, L. M., Krebs, C. and Bollinger, J. M., Jr. Kinetic dissection of the catalytic mechanism of taurine:α-ketoglutarate dioxygenase (TauD) from Escherichia coli. Biochemistry 2005, 44, 8138-8147.
- Husain, M. and Massey, V. Kinetic studies on the reaction of p-hydroxybenzoate hydroxylase. Agreement of steady state and rapid reaction data. J Biol Chem 1979, 254, 6657-6666. [91] Beaty, N. B. and Ballou, D. P. The oxidative half-reaction of liver microsomal FAD-containing monooxygenase. J Biol Chem 1981, 256, 4619-4625. [92] Beaty, N. B. and Ballou, D. P. The reductive half-reaction of liver microsomal FAD-containing monooxygenase. J Biol Chem 1981, 256, 4611-4618. [93]
- Breukink, E. and de Kruijff, B. Lipid II as a target for antibiotics. Nat Rev Drug Discov 2006, 5, 321- 332.
- Frey, P. A. and Reed, G. H. Lysine 2,3-aminomutase and the mechanism of the interconversion of lysine and β-lysine. Adv Enzymol Relat Areas Mol Biol 1993, 66, 1-39.
- Takeuchi, N., Kawakami, M., Omori, A., Ueda, T., Spremulli, L. L. and Watanabe, K. Mammalian mitochondrial methionyl-tRNA transformylase from bovine liver. Purification, characterization, and gene structure. J Biol Chem 1998, 273, 15085-15090.
- Schubert, H. L., Blumenthal, R. M. and Cheng, X. Many paths to methyltransfer: A chronicle of convergence. Trends Biochem Sci 2003, 28, 329-335.
- Mein Dank gilt auch Dr. Markus Oberthür und Peter Schüler für die chemische Synthese der Methyl-Phenylalanin-Standards.
- Sutton, W. B. Mechanism of action and crystallization of lactic oxidative decarboxylase from Mycobacterium phlei. J Biol Chem 1957, 226, 395-405. [76] de Jong, E., Van Berkel, W. J., van der Zwan, R. P. and de Bont, J. A. M. Purification and characterization of vanillyl-alcohol oxidase from Penicillium simplicissimum. A novel aromatic alcohol oxidase containing covalently bound FAD. Eur J Biochem 1992, 208, 651-657. [77] de Lorenzo, V., Bindereif, A., Paw, B. H. and Neilands, J. B. Aerobactin biosynthesis and transport genes of plasmid ColV-K30 in Escherichia coli K-12. J Bacteriol 1986, 165, 570-578. [78]
- Tuderman, L., Myllyla, R. and Kivirikko, K. I. Mechanism of the prolyl hydroxylase reaction. 1. Role of co-substrates. Eur J Biochem 1977, 80, 341-348.
- Strieker, M., Kopp, F., Mahlert, C., Essen, L. O. and Marahiel, M. A. Mechanistic and structural basis of stereospecific Cβ-hydroxylation in calcium-dependent antibiotic, a daptomycin-type lipopeptide. ACS Chem Biol 2007, 2, 187-196.
- Moran, G. R., Entsch, B., Palfey, B. A. and Ballou, D. P. Mechanistic insights into p-hydroxybenzoate hydroxylase from studies of the mutant Ser212Ala. Biochemistry 1999, 38, 6292-6299. [88]
- Einen ganz besonderen Dank möchte ich meinen Eltern und meiner Schwester Nina aussprechen. Meine Eltern haben mich während des gesamten Studiums und der Promotionszeit hervorragend unterstützt und mir viel Rückhalt gegeben. Ohne sie wäre mein Studium so nicht möglich gewesen. Auch meine Schwester Nina ist immer für mich da und wir werden hoffentlich in Zukunft auch noch so viel Spaß haben wie bisher.
- Hoeffler, D. and Zimmermann, U. Methicillin-resistant Staphylococcus aureus and vancomycin- resistant Enterococci. Lancet 1997, 350, 739. [6]
- Marahiel, M. A., Stachelhaus, T. and Mootz, H. D. Modular peptide synthetases involved in nonribosomal peptide synthesis. Chem Rev 1997, 97, 2651-2674. [11] Grunewald, J. and Marahiel, M. A. Chemoenzymatic and template-directed synthesis of bioactive macrocyclic peptides. Microbiol Mol Biol Rev 2006, 70, 121-146. [12]
- Sambrook, J., Fritsch, E. F. and Maniatis, T. Molecular cloning: A laboratory manual. Cold Spring Laboratory press, Cold spring Harbor, NY 1989,
- Baltz, R. H. Molecular engineering approaches to peptide, polyketide and other antibiotics. Nat Biotechnol 2006, 24, 1533-1540.
- Sieber, S. A. and Marahiel, M. A. Molecular mechanisms underlying nonribosomal peptide synthesis: Approaches to new antibiotics. Chem Rev 2005, 105, 715-738. [19]
- Vagin, A. and Teplyakov, A. Molrep: An automated program for molecular replacement. J Appl Cryst 1997, 30, 1022-1025.
- Vaillancourt, F. H., Yeh, E., Vosburg, D. A., Garneau-Tsodikova, S. and Walsh, C. T. Nature's inventory of halogenation catalysts: Oxidative strategies predominate. Chem Rev 2006, 106, 3364-3378.
- Ligon, Novartis Agribusiness Biotechnology Research, Inc., Research Triangle, NC (USA) and NADH oxidase (from Thermus thermiphilus) from Prof. Helmut Erdmann, Fachhochschule Flensburg (Germany). Angew Chem Int Ed Engl 2000, 39, 2300-2302.
- Clardy, J., Fischbach, M. A. and Walsh, C. T. New antibiotics from bacterial natural products. Nat Biotechnol 2006, 24, 1541-1550.
- Koehn, F. E. New strategies and methods in the discovery of natural product anti-infective agents: The mannopeptimycins. J Med Chem 2008, 51, 2613-2617.
- Recktenwald, J., Shawky, R., Puk, O., Pfennig, F., Keller, U., Wohlleben, W. and Pelzer, S. Nonribosomal biosynthesis of vancomycin-type antibiotics: A heptapeptide backbone and eight peptide synthetase modules. Microbiology 2002, 148, 1105-1118.
- Que, L., Jr. One motif--many different reactions. Nat Struct Biol 2000, 7, 182-184.
- Fleming, A. On the antibacterial action of cultures of a penicillium, with special reference to their use in the isolation of B. influenzae. 1929. Bull World Health Organ 2001, 79, 780-790. [3] Walsh, C. Molecular mechanisms that confer antibacterial drug resistance. Nature 2000, 406, 775-781. [4] Chambers, H. F. Methicillin resistance in Staphylococci: Molecular and biochemical basis and clinical implications. Clin Microbiol Rev 1997, 10, 781-791.
- Kopp, F., Mahlert, C., Grunewald, J. and Marahiel, M. A. Peptide macrocyclization: The reductase of the nostocyclopeptide synthetase triggers the self-assembly of a macrocyclic imine. J Am Chem Soc 2006, 128, 16478-16479.
- Abergel, R. J., Zawadzka, A. M. and Raymond, K. N. Petrobactin-mediated iron transport in pathogenic bacteria: Coordination chemistry of an unusual 3,4-catecholate/citrate siderophore. J Am Chem Soc 2008, 130, 2124-2125.
- Velkov, T. and Lawen, A. Photoaffinity labeling of the N-methyltransferase domains of cyclosporin synthetase. Photochem Photobiol 2003, 77, 129-137. [47] de Crecy-Lagard, V., Saurin, W., Thibaut, D., Gil, P., Naudin, L., Crouzet, J. and Blanc, V. Streptogramin B biosynthesis in Streptomyces pristinaespiralis and Streptomyces virginiae: Molecular characterization of the last structural peptide synthetase gene. Antimicrob Agents Chemother 1997, 41, 1904-1909. [48] Schauwecker, F., Pfennig, F., Grammel, N. and Keller, U. Construction and in vitro analysis of a new bi-modular polypeptide synthetase for synthesis of N-methylated acyl peptides. Chem Biol 2000, 7, 287-297.
- Spector, T. and Massey, V. P-hydroxybenzoate hydroxylase from Pseudomonas fluorescens. Evidence for an oxygenated flavin intermediate. J Biol Chem 1972, 247, 5632-5636. [87]
- Walsh, C. T. Polyketide and nonribosomal peptide antibiotics: Modularity and versatility. Science 2004, 303, 1805-1810. [13]
- Lin, Y.-M. and Miller, M. J. Practical synthesis of hydroxamate-derived siderophore components by an indirect oxidation method and synthesis of a dig-siderophore conjugate and a biotin-siderophore conjugate. J Org Chem 1999, 64, 7451-7458.
- Challis, G. L., Ravel, J. and Townsend, C. A. Predictive, structure-based model of amino acid recognition by nonribosomal peptide synthetase adenylation domains. Chem Biol 2000, 7, 211-224.
- Attieh, J. M., Hanson, A. D. and Saini, H. S. Purification and characterization of a novel methyltransferase responsible for biosynthesis of halomethanes and methanethiol in Brassica oleracea. J Biol Chem 1995, 270, 9250-9257.
- Keller, S., Wage, T., Hohaus, K., Holzer, M., Eichhorn, E. and van Pee, K. H. Purification and partial characterization of tryptophan 7-halogenase (PrnA) from Pseudomonas fluorescens this work was supported by the Deutsche Forschungsgemeinschaft (DFG) through the Graduiertenkolleg "Struktur- Eigenschafts-Beziehungen bei Heterocyclen", the environment and climate research and technology development programme of the european union, the Sächsische Staatsministerium für Umwelt und Landesentwicklung, the Max-Buchner-Stiftung, and the Fonds der Chemischen Industrie. Samples of P. Fluorescens BL915DeltaORF1-4 with pPEH14(prnA) and pPEH14(prnC) were obtained from Dr. J. M.
- Howell, L. G., Spector, T. and Massey, V. Purification and properties of p-hydroxybenzoate hydroxylase from Pseudomonas fluorescens. J Biol Chem 1972, 247, 4340-4350. [90]
- Abu-Omar, M. M., Loaiza, A. and Hontzeas, N. Reaction mechanisms of mononuclear non-heme iron oxygenases. Chem Rev 2005, 105, 2227-2252.
- Jones, K. C. and Ballou, D. P. Reactions of the 4a-hydroperoxide of liver microsomal flavin-containing monooxygenase with nucleophilic and electrophilic substrates. J Biol Chem 1986, 261, 2553-2559. [94] Meneely, K. M., Barr, E. W., Bollinger, J. M., Jr. and Lamb, A. L. Kinetic mechanism of ornithine hydroxylase (PvdA) from Pseudomonas aeruginosa: Substrate triggering of O 2 addition but not flavin reduction. Biochemistry 2009, 48, 4371-4376. [95] Hausinger, R. P. FeII/α-ketoglutarate-dependent hydroxylases and related enzymes. Crit Rev Biochem Mol Biol 2004, 39, 21-68. [96]
- Duthaler, R. O. Recent developments in the stereoselective synthesis of -aminoacids. Tetrahedron 1994, 50, 1539-1650.
- Gehring, A. M., Mori, I. and Walsh, C. T. Reconstitution and characterization of the Escherichia coli enterobactin synthetase from EntB, EntE, and EntF. Biochemistry 1998, 37, 2648-2659. [60]
- Fitzi, R. and Seebach, D. Resolution and use in α-amino acid synthesis of imidazolidinone glycine derivatives. Tetrahedron 1988, 44, 5277-5292.
- Youngblood, B., Shieh, F. K., Buller, F., Bullock, T. and Reich, N. O. S-adenosyl-L-methionine- dependent methyl transfer: Observable precatalytic intermediates during DNA cytosine methylation. Biochemistry 2007, 46, 8766-8775.
- Matula, C., Nahler, G. and Kreuzig, F. Salivary levels of gramicidin after use of a tyrothricin-containing gargle/mouth-wash and tyrothricin lozenges. Int J Clin Pharmacol Res 1988, 8, 259-261. [2]
- Martin, J. L. and McMillan, F. M. Sam (dependent) I am: The S-adenosylmethionine-dependent methyltransferase fold. Curr Opin Struct Biol 2002, 12, 783-793.
- Houge-Frydrych, C. S., Gilpin, M. L., Skett, P. W. and Tyler, J. W. SB-203207 and SB-203208, two novel isoleucyl tRNA synthetase inhibitors from a Streptomyces sp. II. Structure determination. J Antibiot (Tokyo) 2000, 53, 364-372.
- Merrifield, R. B. Solid phase peptide synthesis. I. The synthesis of atetrapeptide. J Am Chem Soc 1963, 85, 2149-2152.
- Mahlert, C., Kopp, F., Thirlway, J., Micklefield, J. and Marahiel, M. A. Stereospecific enzymatic transformation of α-ketoglutarate to (2S,3R)-3-methyl glutamate during acidic lipopeptide biosynthesis. J Am Chem Soc 2007, 129, 12011-12018.
- Strieker, M., Nolan, E. M., Walsh, C. T. and Marahiel, M. A. Stereospecific synthesis of threo-and erythro-β-hydroxyglutamic acid during kutzneride biosynthesis. J Am Chem Soc 2009, 131, 13523- 13530. [63]
- Parsons, J. F., Greenhagen, B. T., Shi, K., Calabrese, K., Robinson, H. and Ladner, J. E. Structural and functional analysis of the pyocyanin biosynthetic protein PhzM from Pseudomonas aeruginosa. Biochemistry 2007, 46, 1821-1828.
- Samel, S. A., Schoenafinger, G., Knappe, T. A., Marahiel, M. A. and Essen, L. O. Structural and functional insights into a peptide bond-forming bidomain from a nonribosomal peptide synthetase. Structure 2007, 15, 781-792. [36]
- Conti, E., Stachelhaus, T., Marahiel, M. A. and Brick, P. Structural basis for the activation of phenylalanine in the non-ribosomal biosynthesis of gramicidin S. Embo J 1997, 16, 4174-4183. [20] May, J. J., Kessler, N., Marahiel, M. A. and Stubbs, M. T. Crystal structure of DhbE, an archetype for aryl acid activating domains of modular nonribosomal peptide synthetases. Proc Natl Acad Sci U S A 2002, 99, 12120-12125. [21] Stachelhaus, T., Mootz, H. D. and Marahiel, M. A. The specificity-conferring code of adenylation domains in nonribosomal peptide synthetases. Chem Biol 1999, 6, 493-505. [22] Stachelhaus, T., Huser, A. and Marahiel, M. A. Biochemical characterization of peptidyl carrier protein (PCP), the thiolation domain of multifunctional peptide synthetases. Chem Biol 1996, 3, 913-921. [23]
- Muller, T. A., Zavodszky, M. I., Feig, M., Kuhn, L. A. and Hausinger, R. P. Structural basis for the enantiospecificities of R-and S-specific phenoxypropionate/α-ketoglutarate dioxygenases. Protein Sci 2006, 15, 1356-1368.
- Helmetag, V., Samel, S. A., Thomas, M. G., Marahiel, M. A. and Essen, L. O. Structural basis for the erythro-stereospecificity of the L-arginine oxygenase VioC in viomycin biosynthesis. Febs J 2009, 276, 3669-3682.
- Hojati, Z., Milne, C., Harvey, B., Gordon, L., Borg, M., Flett, F., Wilkinson, B., Sidebottom, P. J., Rudd, B. A., Hayes, M. A., Smith, C. P. and Micklefield, J. Structure, biosynthetic origin, and engineered biosynthesis of calcium-dependent antibiotics from Streptomyces coelicolor. Chem Biol 2002, 9, 1175-1187. [69]
- Castiglione, F., Marazzi, A., Meli, M. and Colombo, G. Structure elucidation and 3D solution conformation of the antibiotic enduracidin determined by NMR spectroscopy and molecular dynamics. Magn Reson Chem 2005, 43, 603-610.
- Zubieta, C., He, X. Z., Dixon, R. A. and Noel, J. P. Structures of two natural product methyltransferases reveal the basis for substrate specificity in plant O-methyltransferases. Nat Struct Biol 2001, 8, 271-279.
- Jones, R. G. Studies on imidazoles. II. The synthesis of 5-imidazolecarboxylates from glycine and substituted glycine esters. J Am Chem Soc 1949, 71, 644-647.
- Nagata, A., Ando, T., Izumi, R., Sakakibara, H. and Take, T. Studies on tuberactinomycin (tuberactin), a new antibiotic. I. Taxonomy of producing strain, isolation and characterization. J Antibiot (Tokyo) 1968, 21, 681-687.
- Zhou, J., Gunsior, M., Bachmann, B. O., Townsend, C. A. and Solomon, E. I. Substrate binding to the α-ketoglutarate-dependent non-heme iron enzyme clavaminate synthase 2: Coupling mechanism of oxidative decarboxylation and hydroxylation. Journal of the American Chemical Society 1998, 120, 13539-13540.
- O'Brien, J. R., Schuller, D. J., Yang, V. S., Dillard, B. D. and Lanzilotta, W. N. Substrate-induced conformational changes in Escherichia coli taurine/α-ketoglutarate dioxygenase and insight into the oligomeric structure. Biochemistry 2003, 42, 5547-5554.
- Challis, G. L. and Hopwood, D. A. Synergy and contingency as driving forces for the evolution of multiple secondary metabolite production by Streptomyces species. Proc Natl Acad Sci U S A 2003, 100 Suppl 2, 14555-14561. [7] Wandersman, C. and Delepelaire, P. Bacterial iron sources: From siderophores to hemophores. Annu Rev Microbiol 2004, 58, 611-647.
- Rossa, B. A. and Viswanatha, T. Synthesis and properties of γ-hydroxyarginine. Can J Biochem 1968, 46, 725-729.
- Clement, B., Schnorwangen, E., Kampchen, T., Mordvintcev, P. and Mulsch, A. Synthesis of 15N ω-hydroxy-L-arginine and ESR and 15N-NMR studies for the elucidation of the molecular mechanism of enzymic nitric oxide formation from L-arginine. Arch Pharm (Weinheim) 1994, 327, 793-798.
- Schracke, N., Linne, U., Mahlert, C. and Marahiel, M. A. Synthesis of linear gramicidin requires the cooperation of two independent reductases. Biochemistry 2005, 44, 8507-8513. [39]
- Mascaro, L., Jr., Horhammer, R., Eisenstein, S., Seller, L. K., Mascaro, K. and Floss, H. G. Synthesis of methionine carrying a chiral methyl group and its use in determining the steric course of the enzymatic C-methylation of indolepyruvate during indolmycin biosynthesis. J Am Chem Soc 1977, 99, 273-274.
- Schade, D., Topker-Lehmann, K., Kotthaus, J. and Clement, B. Synthetic approaches to N(δ)- methylated L-arginine, N(ω)-hydroxy-L-arginine, L-citrulline, and N(δ)-cyano-L-ornithine.
- Walsh, C. T., Chen, H., Keating, T. A., Hubbard, B. K., Losey, H. C., Luo, L., Marshall, C. G., Miller, D. A. and Patel, H. M. Tailoring enzymes that modify nonribosomal peptides during and after chain elongation on NRPS assembly lines. Curr Opin Chem Biol 2001, 5, 525-534. [67]
- Koehntop, K. D., Emerson, J. P. and Que, L., Jr. The 2-His-1-carboxylate facial triad: A versatile platform for dioxygen activation by mononuclear non-heme iron(II) enzymes. J Biol Inorg Chem 2005, 10, 87-93.
- Hornemann, U., Hurley, L. H., Speedie, M. K. and Floss, H. G. The biosynthesis of indolmycin. J Am Chem Soc 1971, 93, 3028-3035.
- Purpero, V. and Moran, G. R. The diverse and pervasive chemistries of the α-keto acid dependent enzymes. J Biol Inorg Chem 2007, 12, 587-601.
- Yin, X. and Zabriskie, T. M. The enduracidin biosynthetic gene cluster from Streptomyces fungicidicus. Microbiology 2006, 152, 2969-2983.
- Coderre, P. E. and Earhart, C. F. The EntD gene of the Escherichia coli K12 enterobactin gene cluster. J Gen Microbiol 1989, 135, 3043-3055.
- Modolell, J. and Vazquez. The inhibition of ribosomal translocation by viomycin. Eur J Biochem 1977, 81, 491-497.
- Kessler, N., Schuhmann, H., Morneweg, S., Linne, U. and Marahiel, M. A. The linear pentadecapeptide gramicidin is assembled by four multimodular nonribosomal peptide synthetases that comprise 16 modules with 56 catalytic domains. J Biol Chem 2004, 279, 7413-7419.
- Miao, V., Brost, R., Chapple, J., She, K., Gal, M. F. and Baltz, R. H. The lipopeptide antibiotic A54145 biosynthetic gene cluster from Streptomyces fradiae. J Ind Microbiol Biotechnol 2006, 33, 129-140.
- Weber, G., Schorgendorfer, K., Schneider-Scherzer, E. and Leitner, E. The peptide synthetase catalyzing cyclosporine production in Tolypocladium niveum is encoded by a giant 45.8-kilobase open reading frame. Curr Genet 1994, 26, 120-125. [17]
- Bitto, E., Bingman, C. A., Allard, S. T., Wesenberg, G. E., Aceti, D. J., Wrobel, R. L., Frederick, R. O., Sreenath, H., Vojtik, F. C., Jeon, W. B., Newman, C. S., Primm, J., Sussman, M. R., Fox, B. G., Markley, J. L. and Phillips, G. N., Jr. The structure at 2.4 Å resolution of the protein from gene locus AT3G21360, a putative Fe(II)/2-oxoglutarate-dependent enzyme from Arabidopsis thaliana. Acta Crystallogr Sect F Struct Biol Cryst Commun 2005, 61, 469-472.
- Luo, L., Kohli, R. M., Onishi, M., Linne, U., Marahiel, M. A. and Walsh, C. T. Timing of epimerization and condensation reactions in nonribosomal peptide assembly lines: Kinetic analysis of phenylalanine activating elongation modules of tyrocidine synthetase B. Biochemistry 2002, 41, 9184-9196. [44]
- Robbel, L., Hoyer, K. M. and Marahiel, M. A. TioS T-TE--a prototypical thioesterase responsible for cyclodimerization of the quinoline-and quinoxaline-type class of chromodepsipeptides. Febs J 2009, 276, 1641-1653. [61]
- Hruby, V. J., Toth, G., Gehrig, C. A., Kao, L. F., Knapp, R., Lui, G. K., Yamamura, H. I., Kramer, T. H., Davis, P. and Burks, T. F. Topographically designed analogs of [cyclic] [D-Pen2,D- Pen5]enkephalin. Journal of Medicinal Chemistry 1991, 34, 1823-1830.
- Cardillo, G., Gentilucci, L. and Tolomelli, A. Unusual amino acids: Synthesis and introduction into naturally occurring peptides and biologically active analogues. Mini Rev Med Chem 2006, 6, 293-304.
- Thieriet, N., Alsina, J., Giralt, E., Guibé, F. and Albericio, F. Use of alloc-amino acids in solid-phase peptide synthesis. Tandem deprotection-coupling reactions using neutral conditions. Tetrahedron Lett. 1997, 38, 7275-7278.
- Stein, D. B., Linne, U. and Marahiel, M. A. Utility of epimerization domains for the redesign of nonribosomal peptide synthetases. Febs J 2005, 272, 4506-4520.
- Carter-Franklin, J. N. and Butler, A. Vanadium bromoperoxidase-catalyzed biosynthesis of halogenated marine natural products. J Am Chem Soc 2004, 126, 15060-15066.
- Hubbard, B. K. and Walsh, C. T. Vancomycin assembly: Nature's way. Angew Chem Int Ed Engl 2003, 42, 730-765. [38]
- Yin, X. and Zabriskie, T. M. Vioc is a non-heme iron, α-ketoglutarate-dependent oxygenase that catalyzes the formation of 3S-hydroxy-L-arginine during viomycin biosynthesis. Chembiochem 2004, 5, 1274-1277.
- Bartz, Q. R., Ehrlich, J., Mold, J. D., Penner, M. A. and Smith, R. M. Viomycin, a new tuberculostatic antibiotic. Am Rev Tuberc 1951, 63, 4-6.
- Yamada, T. and Bierhaus, K. H. Viomycin favours the formation of 70S ribosome couples. Mol Gen Genet 1978, 161, 261-265.
- Mootz, H. D., Schwarzer, D. and Marahiel, M. A. Ways of assembling complex natural products on modular nonribosomal peptide synthetases. Chembiochem 2002, 3, 490-504. [18]
- Neary, J. M., Powell, A., Gordon, L., Milne, C., Flett, F., Wilkinson, B., Smith, C. P. and Micklefield, J. An asparagine oxygenase (AsnO) and a 3-hydroxyasparaginyl phosphotransferase (HasP) are involved in the biosynthesis of calcium-dependent lipopeptide antibiotics. Microbiology 2007, 153, 768-776.
- Stehr, M., Diekmann, H., Smau, L., Seth, O., Ghisla, S., Singh, M. and Macheroux, P. A hydrophobic sequence motif common to N-hydroxylating enzymes. Trends Biochem Sci 1998, 23, 56-57.
- Shi, R., Lamb, S. S., Zakeri, B., Proteau, A., Cui, Q., Sulea, T., Matte, A., Wright, G. D. and Cygler, M. Structure and function of the glycopeptide N-methyltransferase MtfA, a tool for the biosynthesis of modified glycopeptide antibiotics. Chem Biol 2009, 16, 401-410.
- Cosmina, P., Rodriguez, F., de Ferra, F., Grandi, G., Perego, M., Venema, G. and van Sinderen, D. Sequence and analysis of the genetic locus responsible for surfactin synthesis in Bacillus subtilis. Mol Microbiol 1993, 8, 821-831. [59]
- Windahl, M. S., Petersen, C. R., Christensen, H. E. and Harris, P. Crystal structure of tryptophan hydroxylase with bound amino acid substrate. Biochemistry 2008, 47, 12087-12094.
- Zocher, R., Nihira, T., Paul, E., Madry, N., Peeters, H., Kleinkauf, H. and Keller, U. Biosynthesis of cyclosporin A: Partial purification and properties of a multifunctional enzyme from Tolypocladium inflatum. Biochemistry 1986, 25, 550-553. [50]
- Heemstra, J. R., Walsh, C. T. and Sattely, E. S. Enzymatic tailoring of ornithine in the biosynthesis of the rhizobium cyclic trihydroxamate siderophore vicibactin. J Am Chem Soc 2009, 131, 15317-15329.
- Samel, S. A., Marahiel, M. A. and Essen, L. O. How to tailor non-ribosomal peptide products--new clues about the structures and mechanisms of modifying enzymes. Mol Biosyst 2008, 4, 387-393.
- Zhang, Z., Ren, J., Stammers, D. K., Baldwin, J. E., Harlos, K. and Schofield, C. J. Structural origins of the selectivity of the trifunctional oxygenase clavaminic acid synthase. Nat Struct Biol 2000, 7, 127- 133.
- Emsley, P. and Cowtan, K. Coot: Model-building tools for molecular graphics. Acta Crystallogr D Biol Crystallogr 2004, 60, 2126-2132.
- Carter, R. A., Worsley, P. S., Sawers, G., Challis, G. L., Dilworth, M. J., Carson, K. C., Lawrence, J. A., Wexler, M., Johnston, A. W. and Yeoman, K. H. The vbs genes that direct synthesis of the siderophore vicibactin in Rhizobium leguminosarum: Their expression in other genera requires ECF sigma factor RpoI. Mol Microbiol 2002, 44, 1153-1166.
- Challis, G. L. Mining microbial genomes for new natural products and biosynthetic pathways. Microbiology 2008, 154, 1555-1569.
- Barona-Gomez, F., Lautru, S., Francou, F. X., Leblond, P., Pernodet, J. L. and Challis, G. L. Multiple biosynthetic and uptake systems mediate siderophore-dependent iron acquisition in Streptomyces coelicolor A3(2) and Streptomyces ambofaciens ATCC 23877. Microbiology 2006, 152, 3355-3366.
- Lautru, S., Deeth, R. J., Bailey, L. M. and Challis, G. L. Discovery of a new peptide natural product by Streptomyces coelicolor genome mining. Nat Chem Biol 2005, 1, 265-269. [62]
- Lakowski, T. M. and Frankel, A. A kinetic study of human protein arginine N-methyltransferase 6 reveals a distributive mechanism. J Biol Chem 2008, 283, 10015-10025.
- Keating, T. A., Marshall, C. G., Walsh, C. T. and Keating, A. E. The structure of VibH represents nonribosomal peptide synthetase condensation, cyclization and epimerization domains. Nat Struct Biol 2002, 9, 522-526. [35]
- Wang, Z. X., Li, S. M. and Heide, L. Identification of the coumermycin A(1) biosynthetic gene cluster of Streptomyces rishiriensis DSM 40489. Antimicrob Agents Chemother 2000, 44, 3040-3048.
- [26] Schwarzer, D., Mootz, H. D., Linne, U. and Marahiel, M. A. Regeneration of misprimed nonribosomal peptide synthetases by type II thioesterases. Proc Natl Acad Sci U S A 2002, 99, 14083-14088. [27]
- Magarvey, N. A., Haltli, B., He, M., Greenstein, M. and Hucul, J. A. Biosynthetic pathway for mannopeptimycins, lipoglycopeptide antibiotics active against drug-resistant gram-positive pathogens. Antimicrob Agents Chemother 2006, 50, 2167-2177.
- Singh, M. P., Petersen, P. J., Weiss, W. J., Janso, J. E., Luckman, S. W., Lenoy, E. B., Bradford, P. A., Testa, R. T. and Greenstein, M. Mannopeptimycins, new cyclic glycopeptide antibiotics produced by Streptomyces hygroscopicus LL-AC98: Antibacterial and mechanistic activities. Antimicrob Agents Chemother 2003, 47, 62-69.
- Hoffart, L. M., Barr, E. W., Guyer, R. B., Bollinger, J. M., Jr. and Krebs, C. Direct spectroscopic detection of a C-H-cleaving high-spin Fe(IV) complex in a prolyl-4-hydroxylase. Proc Natl Acad Sci U S A 2006, 103, 14738-14743.
- Ehmann, D. E., Shaw-Reid, C. A., Losey, H. C. and Walsh, C. T. The EntF and EntE adenylation domains of Escherichia coli enterobactin synthetase: Sequestration and selectivity in acyl-AMP transfers to thiolation domain cosubstrates. Proc Natl Acad Sci U S A 2000, 97, 2509-2514. [29]
- Lee, P. T., Hsu, A. Y., Ha, H. T. and Clarke, C. F. A C-methyltransferase involved in both ubiquinone and menaquinone biosynthesis: Isolation and identification of the Escherichia coli UbiE gene. J Bacteriol 1997, 179, 1748-1754.
- Mootz, H. D. and Marahiel, M. A. The tyrocidine biosynthesis operon of Bacillus brevis: Complete nucleotide sequence and biochemical characterization of functional internal adenylation domains. J Bacteriol 1997, 179, 6843-6850. [57]
- Muller, C., Nolden, S., Gebhardt, P., Heinzelmann, E., Lange, C., Puk, O., Welzel, K., Wohlleben, W. and Schwartz, D. Sequencing and analysis of the biosynthetic gene cluster of the lipopeptide antibiotic friulimicin in Actinoplanes friuliensis. Antimicrob Agents Chemother 2007, 51, 1028-1037.
- Thomas, M. G., Chan, Y. A. and Ozanick, S. G. Deciphering tuberactinomycin biosynthesis: Isolation, sequencing, and annotation of the viomycin biosynthetic gene cluster. Antimicrob Agents Chemother 2003, 47, 2823-2830.
- Guo, H. B. and Guo, H. Mechanism of histone methylation catalyzed by protein lysine methyltransferase SET7/9 and origin of product specificity. Proc Natl Acad Sci U S A 2007, 104, 8797- 8802.
- Thariath, A., Socha, D., Valvano, M. A. and Viswanatha, T. Construction and biochemical characterization of recombinant cytoplasmic forms of the IucD protein (lysine:N6-hydroxylase) encoded by the pColV-K30 aerobactin gene cluster. J Bacteriol 1993, 175, 589-596.
- Wierenga, R. K., de Jong, R. J., Kalk, K. H., Hol, W. G. and Drenth, J. Crystal structure of p-hydroxybenzoate hydroxylase. J Mol Biol 1979, 131, 55-73. [85]
- Miethke, M. and Marahiel, M. A. Siderophore-based iron acquisition and pathogen control. Microbiol Mol Biol Rev 2007, 71, 413-451.
- Chance, M. R., Bresnick, A. R., Burley, S. K., Jiang, J. S., Lima, C. D., Sali, A., Almo, S. C., Bonanno, J. B., Buglino, J. A., Boulton, S., Chen, H., Eswar, N., He, G., Huang, R., Ilyin, V., McMahan, L., Pieper, U., Ray, S., Vidal, M. and Wang, L. K. Structural genomics: A pipeline for providing structures for the biologist. Protein Sci 2002, 11, 723-738.
- Dimise, E. J., Widboom, P. F. and Bruner, S. D. Structure elucidation and biosynthesis of fuscachelins, peptide siderophores from the moderate thermophile Thermobifida fusca. Proc Natl Acad Sci U S A 2008, 105, 15311-15316.
- Kovaleva, E. G. and Lipscomb, J. D. Versatility of biological non-heme Fe(II) centers in oxygen activation reactions. Nat Chem Biol 2008, 4, 186-193.
- Barkei, J. J., Kevany, B. M., Felnagle, E. A. and Thomas, M. G. Investigations into viomycin biosynthesis by using heterologous production in Streptomyces lividans. Chembiochem 2009, 10, 366- 376.
- Fei, X., Yin, X., Zhang, L. and Zabriskie, T. M. Roles of VioG and VioQ in the incorporation and modification of the capreomycidine residue in the peptide antibiotic viomycin. J Nat Prod 2007, 70, 618-622.
- Li, S., Anzai, Y., Kinoshita, K., Kato, F. and Sherman, D. H. Functional analysis of MycE and MycF, two O-methyltransferases involved in the biosynthesis of mycinamicin macrolide antibiotics. Chembiochem 2009, 10, 1297-1301.
- You, Z., Omura, S., Ikeda, H., Cane, D. E. and Jogl, G. Crystal structure of the non-heme iron dioxygenase PtlH in pentalenolactone biosynthesis. J Biol Chem 2007, 282, 36552-36560.
- Ruzin, A., Singh, G., Severin, A., Yang, Y., Dushin, R. G., Sutherland, A. G., Minnick, A., Greenstein, M., May, M. K., Shlaes, D. M. and Bradford, P. A. Mechanism of action of the mannopeptimycins, a novel class of glycopeptide antibiotics active against vancomycin-resistant gram-positive bacteria. Antimicrob Agents Chemother 2004, 48, 728-738.
- Lomri, N., Gu, Q. and Cashman, J. R. Molecular cloning of the flavin-containing monooxygenase (form II) cDNA from adult human liver. Proc Natl Acad Sci U S A 1992, 89, 1685-1689.
- Gellert, M., O'Dea, M. H., Itoh, T. and Tomizawa, J. Novobiocin and coumermycin inhibit DNA supercoiling catalyzed by DNA gyrase. Proc Natl Acad Sci U S A 1976, 73, 4474-4478. [70] Vaillancourt, F. H., Yin, J. and Walsh, C. T. SyrB2 in syringomycin E biosynthesis is a nonheme FeII α-ketoglutarate-and O 2 -dependent halogenase. Proc Natl Acad Sci U S A 2005, 102, 10111-10116. [71]
- Schmitt, E., Blanquet, S. and Mechulam, Y. Structure of crystalline Escherichia coli methionyl- tRNA(f)Met formyltransferase: Comparison with glycinamide ribonucleotide formyltransferase. Embo J 1996, 15, 4749-4758.
- Puk, O., Bischoff, D., Kittel, C., Pelzer, S., Weist, S., Stegmann, E., Sussmuth, R. D. and Wohlleben, W. Biosynthesis of chloro-β-hydroxytyrosine, a nonproteinogenic amino acid of the peptidic backbone of glycopeptide antibiotics. J Bacteriol 2004, 186, 6093-6100.
- Hahn, M. and Stachelhaus, T. Selective interaction between nonribosomal peptide synthetases is facilitated by short communication-mediating domains. Proc Natl Acad Sci U S A 2004, 101, 15585- 15590. [45]
- Kozbial, P. Z. and Mushegian, A. R. Natural history of S-adenosylmethionine-binding proteins. BMC Struct Biol 2005, 5, 19.
- Xian, M., Alaux, S., Sagot, E. and Gefflaut, T. Chemoenzymatic synthesis of glutamic acid analogues: Substrate specificity and synthetic applications of branched chain aminotransferase from Escherichia coli. J Org Chem 2007, 72, 7560-7566.