Halogenating enzymes for selective halogenation reactions

Current Organic Chemistry

Volumn 16, Issue 21, 2012, Pages 2583-2597

  van Pée, Karl Heinz ^a  

^a DRESDEN UNIVERSITY OF TECHNOLOGY   (Germany)

Author keywords

Halogenase; Haloperoxidase; Hypohalous acid; Non heme iron; Radical mechanism; Regioselectivity

Indexed keywords

ABSTRACTING; COORDINATION REACTIONS; HALOGENATION; IRON COMPOUNDS; PORPHYRINS; SUBSTRATES;

ACTIVE SITE; CATALYSE; HALOGENASE; HALOPEROXIDASE; HEME IRON; HYDROPEROXIDES; HYPOHALOUS ACIDS; NON-HEME IRON; PRODUCT FORMATION; RADICAL MECHANISM;

REGIOSELECTIVITY;

EID: 84872580413     PISSN: 13852728     EISSN: None     Source Type: Journal    
DOI: 10.2174/138527212804004607     Document Type: Article

References (100)

1. Schmittinger, P. Chlorine, Wiley-VC H: Weinheim, 2000.
2. Petty, M.A. An introduction to the origin and biochemistry of microbial halometabolites. Bacteriol. Rev. 1961, 25 111-130.
3. Gribble, G. W. 2010 Naturally occurring organohalogen compounds-A comprehensive update. In "Progress in the Chemistry of Organic Natural Products" (Kinhorn A. D., Falk H., Kobayashi J. (eds.). Vol. 91, Springer, Wien, New York.
4. Fowden, F.R.S. The occurrence and metabolism of carbon-halogen compounds. Proc. Roy. Soc. B 1968, 171, 5-18.
5. McCormick, J.R. D; Tetracyclines. In Antibiotics; Gottlieb, Shaw, Eds.; Springer: Berlin, Heidelberg, New York, 1967; Vol. 2, pp. 113-122.
6. Shaw, P.D.; Hager, L.P. Biological chlorination. VI. Chloroperoxidase: a component of the β-ketoadipiate chlorinase system. J. Biol. Chem. 1961, 236, 1626-1630.
7. Neidleman, S.L.; Geigert, J. Biohalogenation: Principles, basic roles and applications. Ellis Horwood: Chichester, 1986.
8. Bakkenist, A.R.J.; De Boer, J.E.G.; Plat, H.; Wever, R. The halide complexes of myeloperoxidase and the mechanism of the halogenation reactions. Biochim. Biophys. Acta 1980, 613, 337-348.
9. Harrison, J.E.; Schultz, J. Studies on the chlorinating activity of myeloperoxidase. J. Biol. Chem. 1976, 251, 1371-1374.
10. Sundaramoorthy, M.; Terner, J.; Poulos, T. L. Stereochemistry of the chloroperoxidase active site: crystallographic and molecular-modeling studies. Chem. Biol. 1998, 5, 461-473.
11. Kühnel, K.; Blankenfeld, W.; Terner, J.; Schlichting, I. Crystal structure of chloroperoxidase with its bound substrates and complexed with formate, acetate, and nitrate. J. Biol. Chem. 2006, 281, 23990-13998.
12. Morris, D.R.; Hager, L.P. Chloroperoxidase. I. Isolation and properties of the crystalline glycoprotein. J. Biol. Chem. 1966, 241, 1763-1768.
13. van Pée, K.-H. Biosynthesis of halogenated metabolites by bacteria. Annu. Rev. Microbiol. 1966, 50, 375-399.
14. Vilter, H. Peroxidase from Phaeophyceae. A vanadium(V)-dependent peroxidase from Ascophyllum nodosum. Phytochem. 1984, 23, 1387-1390.
15. Winter, J.M.; Moore, B.S. Exploring the chemistry and biology of vanadiumdependent haloperoxidases. J. Biol. Chem. 2009, 284, 18577-18581.
16. Messerschmidt, A.; Wever, R. X-ray structure of a vanadium-containing enzyme: chloroperoxidase from the fungus Curvularia inaequalis. Proc. Natl. Acad. Sci. USA 1996, 93, 392-396.
17. Messerschmidt, A.; Prade, L.; Wever, R. Implications for the catalytic mechanism of the vanadium-containing enzyme chloroperoxidase from the fungus Curvularia inaequalis by X-ray structure of the native and peroxide form. J. Biol. Chem. 1997, 378, 309-315.
18. Butler, A.; Carter-Franklin, J.N. The role of vanadium bromoperoxidase in the biosynthesis of halogenated marine natural products. Nat. Prod. Rep. 2004, 21, 180-188.
19. Littlechild, J.; Garcia-Rodriguez, E.; Dalby, E.; Isupov, M. Structural and functional comparisons between vanadium haloperoxidases and acid phosphatase enzymes. J. Mol. Recognit. 2002, 15, 291-296.
20. Tanaka, N.; Dumay, V.; Liao, Q.; Lange, A.J.; Wever, R. Bromoperoxidase activity of vanadium-substituted acid phosphatases from Shigella flexneri and Salmonella enteriac ser. typhimuriumt. Eur. J. Biochem. 2002, 269, 2162-2167.
21. Carter-Franklin, J.N.; Butler, A. Vanadium bromoperoxidase-catalyzed biosynthesis of halogenated marine natural products. J. Am. Chem. Soc. 2004, 126, 15060-15066.
22. Bernhardt, P.; Okino, T.; Winter, J.W.; Miyanaga, A.; Moore, B.S. A stereoselective vanadium-dependent chloroperoxidase in bacterial antibiotic biosynthesis. J. Am. Chem. Soc. 2011, 133, 4268-4270.
23. van Pée, K.-H; Keller, S.; Wage, T.; Wynands, I.; Schnerr, H.; Zehner, S. Enzymatic halogenation catalyzed via a catalytic triad and by oxidoreductases. Biol. Chem. 2000, 381, 1-5.
24. Haag, T.; Lingens, F.; van Pée, K.-H. A metal-ion-and cofactor-independent enzymatic redox reaction: Halogenation by bacterial nonheme haloperoxidases. Angew. Chem. Int. Ed. Engl. 1991, 30, 1487-1488.
25. Hecht, H.J.; Sobek, H.; Haag, T.; Pfeifer, O.; van Pée, K.-H. The metal-ionfree oxidoreductase from Streptomyces aureofaciens has an a/β hydrolase fold. Nat. Struct. Biol. 1994, 1, 532-537.
26. 2 by the formation of peracetic acid. Angew. Chem. Int. Ed. Engl. 1997, 36, 1196-1199.
27. Hofmann, B.; Tölzer, S.; Pelletier, I.; Altenbuchner, J.; van Pée, K.-H.; Hecht, H.J. Structural investigations of the cofactor-free chloroperoxidases. J. Mol. Biol., 1998, 279, 889-900.
28. Bernhardt, P.; Hult, K.; Kazlauskas, R.J. Molecular basis of perhydrolase activity in serine hydrolases. Angew. Chem. Int. Ed. 2005, 44, 2742-2746.
29. Dairi, T.; Nakano, T.; Aisaka, K.; Katsumata, R.; Hasegawa, M. Cloning and nucleotide sequence of the gene responsible for chlorination of tetracycline. Biosci. Biotech. Biochem. 1995, 59, 1099-1106.
30. Hammer, P.E.; Hill, D.S.; Lam, S.T.; van Pée, K.-H.; Ligon, J.M. Four genes from Pseudomonas fluorescens that encode the biosynthesis of pyrrolnitrin. Appl. Environ. Microbiol. 1997, 63, 2147-2154.
31. van Pée, K.-H.; Salcher, O.; Lingens, F. Formation of pyrrolnitrin and 3-(2-amino-3-chlorophenyl)pyrrole from 7-chlorotryptophan. Angew. Chem. Int. Ed. Engl. 1980, 19, 828-829.
32. Kirner, S.; Hammer, P.E.; Hill, D.S.; Altmann, A.; Fischer, I.; Weislo, L.J.; Lanahan, M.; van Pée, K.-H.; Ligon, J.M. Functions encoded by pyrrolnitrin biosynthetic genes from Pseudomonas fluorescens. J. Bacteriol. 1998, 180, 1939-1943.
33. Hohaus, K.; Altmann, A.; Burd, W.; Fischer, I.; Hammer, P.E.; Hill, D.S.; Ligon, J.M.; van Pée, K.-H. NADH-dependent halogenases are more likely to be involved in halometabolite biosynthesis than haloperoxidases. Angew. Chem. Int. Ed. Engl. 1997, 36, 2012-2013.
34. Hohaus, K. Nachweis und Anreicherung einer neuartigen Monodechloraminopyrrolnitrin-Halogenase. PhD Thesis, Technische Universität Dresden: Dresden, 1998.
35. Keller, S.; Wage, T.; Hohaus, K.; Hölzer, M.; Eichhorn, E.; van Pée, K.-H. Purification and partial characterization of tryptophan 7-halogenase (PrnA) from Pseudomonas fluorescens. Angew. Chem. Int. Ed. 2000, 39, 2300-2302.
36. Eichhorn, E.; van der Ploeg, J.R.; Leisinger, T. Characterization of a twocomponent alkanesulfonate monooxygenase from Escherichia coli. J. Biol. Chem. 1999, 274, 26639-26646.
37. Hecht, H.J.; Erdmann, H.; Park, H.J.; Sprinzl, M.; Schmid, R.D. Crystal structure of NADH oxidase from Thermus thermophilus. Nat. Struct. Biol. 1995, 2, 1109-14.
38. 2-dependence of tryptophan 7-halogenase. Adv. Synth. Catal. 2005, 347, 1163-1167.
39. Yeh, E.; Garneau, S.; Walsh, C.T. Robust in vitro activity of RebF and RebH, a two-component reductase/halogenase, generating 7-chlorotryptophan during rebeccamycin biosynthesis. Proc. Natl. Acad. Sci. USA 2005, 102, 3960-3965.
40. Zehner, S.; Bister, B.; Süssmuth, R.D.; Méndez, C.; Salas, J.A.; van Pée, K.-H. A regioselective tryptophan 5-halogenase is involved in pyrroindomycin biosynthesis in Streptomyces rugosporus LL-42D005. Chem. Biol. 2005, 12, 445-452.
41. Seibold, C.; Schnerr, H.; Rumpf, J.; Kunzendorf, A.; Hatscher, C.; Wage, T.; Ernyei, A.J.; Dong, C.; Naismith, J.H.; van Pée, K.-H. A flavin-dependent tryptophan 6-halogenase and its use in modification of pyrrolnitrin biosynthesis. Biocat. Biotrans. 2006, 24, 401-408.
42. Lin, S.; Van Lanen, S.G.; Shen, B. Regiospecific chlorination of (S)-β-tyrosyl-S-carrier protein catalyzed by SgcC3 in the biosynthesis of the enediyne antitumor antibiotic C-1027. J. Am. Chem. Soc. 2007, 129, 12432-12438.
43. van Pée, K.-H.; Patallo, E:P. Flavin-dependent halogenases involved in secondary metabolism in bacteria. Appl. Microbiol. Biotechnol. 2006, 70, 631-641.
44. van Pée, K.-H.; Dong, C.; Flecks, S.; Naismith, J.H.; Patallo, E.P.; Wage, T. Biological halogenation has moved far beyond haloperoxidases. Adv. Appl. Microbiol. 2006, 59, 127-157.
45. Sanchez, C.; Butovich, I.A.; Brana, A.F.; Rohr, J.; Méndez, C.; Salas, J.A. The biosynthetic gene cluster for the antitumor rebeccamycin. Characterization and generation of indolocarbazole derivatives. Chem. Biol. 2002, 9, 519-531.
46. Ding, W.; Williams, D.R.; Nothcote, P.; Siegel, M.M.; Tsao, R.; Ashcroft, J.; Morton, G.O.; Alluri, M.; Abbanat, D.; Maiese, W.M.; Ellestad, G.A. Pyrroindomycins, novel antibiotics produced by Streptomyces rugosporus sp. LL-42D005. Isolation and structure determination. J. Antibiotics 1994, 47, 1250-1257.
47. Nowak-Thompson, B.; Chaney, N.; Wing, J.W.; Gold, S.J.; Loper, J.E. Characterization of the pyoluteorin biosynthetic gene cluster of Pseudomonas fluorescens Pf-5. J. Bacteriol. 1999, 181, 2166-2174.
48. 2-dependent halogenase PltA during pyoluteorin biosynthesis. Proc. Natl. Acad. Sci. USA 2005, 102, 13843-13848.
49. Cavalleri, B.; Volpe, G.; Tuan, G.; Berti, M.; Parenti, F. A chlorinated phenylpyrrole antibiotic from Actinoplanes. Curr. Microbiol. 1978, 1, 319-324.
50. Wynands, I.; van Pée, K.-H. A novel halogenase gene from the pentachloropseudilin producer Actinoplanes sp. ATCC 33002 and detection of in vitro halogenase activity. FEMS Microbiol. Lett. 2004, 237, 363-367.
51. Hubbard, B.K.; Walsh C.T. Vancomycin assembly: Nature's way. Angew. Chem. Int. Ed. 2003, 42, 730-765.
52. Dong C.; Flecks, S.; Unversucht, S.; Haupt, C.; van Pée, K.-H.; Naismith, J.H. Tryptophan 7-halogenase structure suggests a mechanism for regioselective chlorination. Science 2005, 309, 2216-2219.
53. Flecks, S.; Patallo, E.P.; Zhu, X.; Ernyei, A.J.; Seifert, G.;. Schneider, A.; Dong, C.; Naismith, J.H.; van Pée, K.-H. New insights into the mechanism of enzymatic chlorination of tryptophan. Angew. Chem. Int. Ed. 2008, 47, 9533-9536.
54. Yeh, E.; Blasiak, L.C., Koglin, A.; Drennan, C.L.; Walsh, C.T. Chlorination by a long-lived intermediate in the mechanism of flavin-dependent halogenases. Biochemistry 2007, 46, 1284-1292.
55. Morrison, M.; Schonbaum, G.R. Peroxidase-catalyzed halogenation. Ann. Rev. Biochem. 1976, 45, 861-887.
56. Lang, A.; Polnick, S., Nicke, T.; William, P.; Patallo, E.P.; Naismith, J.H.; van Pée, K.-H. Changing the regioselectivity of the tryptophan 7-halogenase PrnA by site-directed mutagenesis. Angew. Chem. Int. Ed. 2011, 50, 2951-2953.
57. Yeh, E.; Blasiak, L.C.; Koglin, A.; Drennan, C.L.; Walsh, C.T. Chlorination by a long-lived intermediate in the mechanism of flavin-dependent halogenases. Biochemistry 2007, 46, 1284-1292.
58. Bitto, E.; Huang, Y.; Bingman, C.A.; Singh, S.; Thorson, J.S.; Phillips G.N., Jr. The structure of flavin-dependent tryptophan 7-halogenase RebH. Proteins 2008, 70, 289-293.
59. Zhu, X.; De Laurentis, W.; Leang, K.; Herrmann, J.; Ihlefeld, K.; van Pée, K.-H.; Naismith, J.H. Structural insights in the regioselectivity in the enzymatic chlorination of tryptophan. J. Mol. Biol. 2009, 391, 74-85.
60. Hölzer, M.; Burd, W.; Reißig, H.-U.; van Pée, K.-H. Substrate specificity and regioselectivity of tryptophan 7-halogenase from Pseudomonas fluorescens BL915. Adv. Syn. Catal. 2001, 343, 591-595.
61. Glenn, W.S.; Nims, E.; O'Connor, S.E. Reengineering a tryptophan halogenase to preferentially chlorinate a direct alkaloid precursor. J. Am. Chem. Soc. 2011, 133, 19346-19349.
62. 2-dependent halogenases KtzQ and KtzR produce 6,7-dichlorotryptophan for kutzneride assembly. J. Am. Chem. Soc. 2008, 130, 14024-14025.
63. Zeng, J.; Zhan, J. Characterization of a tryptophan 6-halogenase from Streptomyces toxytricini. Biotechnol. Lett. 2011, 33, 1607-1613.
64. Rachid, S.; Krug, D.; Kunze, B.; Kochems, I.; Scharfe, M.; Zabriskie, T.M.; Blöcker, H.; Müller, R. Molecular and biochemical studies of chondramide formation-highly cytotoxic natural products from Chondromyces crocatus Cm c5. Chem. Biol. 2006, 14, 667-681.
65. Thomas, M.G.; Burkart, M.D.; Walsh, C.T. Conversion of L-proline to pyrrolyl-1-carboxylic-S-PCP during undecylprodigiosin and pyoluteorin biosynthesis. Chem. Biol. 2002, 9 171-184.
66. Buedenbender, S.; Rachid, S.; Müller, R.; Schulz, G.E. Structure and action of the myxobacterial chondrochloren halogenase CndH: a new variant of FAD-dependent halogenases. J. Mol. Biol. 2009, 16, 520-530.
67. Podzelinska, K.; Latimer, R.; Bhattacharya, A.; Vining, L.C.; Zechel, D.L.; Jia, Z. Chloramphenicol biosynthesis: the structure of CmlS, a flavindependent halogenase showing a covalent flavin-aspartate bond. J. Mol. Biol. 2010, 397, 316-331.
68. Reeves, C.D.; Hu, Z.; Reid, R.; Kealey, J.T. Genes for the biosynthesis of the fungal polyketides hypothemycin from Hypomyces subiculosus and radicicol from Pochonia chlamydosporia. Appl. Environ. Microbio. 2008, 74, 5121-5129.
69. Wang, S.; Xu, Y.; Maine, E.A.; Wijeratne, E.M.K.; Espinosa-Artiles, P.; Gunatilaka, A.A.L.; Molnar, I. Functional characterization of the biosynthesis of radiciol, an Hsp90 inhibitor resorcylic acid lactone from Chaetomium chiversii. Chem. Biol. 2008, 15, 1328-1338.
70. Zeng, J.; Zhan, J. A novel fungal flavin-dependent halogenase for natural product biosynthesis. ChemBioChem 2010, 11, 2119-2123.
71. Neumann; C.S.; Walsh, C.T.; Kay, R.R. A flavin-dependent halogenase catalyzes the chlorination step in the biosynthesis of Dictyostelium differentiation-inducing factor 1. Proc. Natl. Acad. Sci. USA 2010, 107, 5798-5803.
72. Sitachitta, N.; Rossi, J.; Roberts, M.A.; Gerwick, W.H.; Fletscher, M.D.; Willis, C.L. Biosynthesis of the marine cyanobacterial metabolite barbamide. 1. Origin of the trichloromethyl group. J. Am. Chem. Soc. 1998, 120, 7131-7132.
73. Sitachitta, N.; Márquez, B.L.; Williamson, R.T.; Rossi, J.; Roberts, M.A.; Gerwick, W.H.; Nguyen, V.-A.; Willis, C.L. Biosynthetic pathway and origin of the chlorinated methyl group in barbamide and dechlorobarbamide, metabolites from the marine cyanobacterium Lyngbya majuscule. Tetrahedron 2000, 56, 9103-9113.
74. Chang, Z.; Flatt, P.; Gerwick, W.H.; Nguyen, V.-A.; Willis, C.L.; Sherman, D.H. The barbamide biosynthetic gene cluster: a novel marine cyanobacterial system of mixed polyketide synthase (PKS)-non-ribosomal peptide synthetase (NRPS) origin involving an unusual trichloroleucyl starter unit. Gene 2002, 296, 235-247.
75. Guenzu, E.; Galli, G.; Grguina, G.; Gross, D.C.; Grandi, G. Characterization of the syringomycin synthetase gene cluster. A link between prokaryotic and eukaryotic peptide synthetases. J. Biol. Chem. 1998, 273, 32857-32863.
76. Ullrich, M.; Bender, C.L. The biosynthetic gene cluster for coronamic acid, an ethylcyclopropyl amino acid, contains genes homologous to amino acidactivating enzymes and thioesterases. J. Bacteriol. 1994, 176, 7574-7586.
77. Ridley, C.P.; Bergquist, P.R.; Harper, M.K.; Faulkner, D.J.; Hooper, J.N.A.; Haygood, M.G. Speciation and biosynthetic variation in four Dictioceratid sponges and their cyanobacterial symbiont, Oscillatoria spongellae. Chem. Biol. 2005, 12, 397-406.
78. Vaillancourt, F.H.; Yeh, E.; Vosburg, D.A.; O'Connor, S.; Walsh, C.T. Cryptic chlorination by a non-haem iron enzyme during cyclopropyl amino acid biosynthesis. Nature 2005, 463, 1191-1194.
79. Hegg, E.L.; Que, L. Jr. The 2-His-1-carboxylate facial triad-an emerging structural motif in mononuclear non-heme iron(II) enzymes. Eur. J. Biochem. 1997, 250, 625-629.
80. Koehntop, K.D.; Emerson, J.P.; 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.
81. 2-dependent halogenase. Proc. Natl. Acad. Sci. USA 2005, 102, 10111-10116.
82. Galonic, D.P.; Vaillancourt, F.H.; Walsh, C.T. Halogenation of unactivated carbon centers in natural product biosynthesis: trichlorination of leucine during barbamide biosynthesis. J. A. Chem. Soc. 2006, 128, 3900-3901.
83. Blasiak, L.C.; Vaillancourt, F.H.; Walsh, C.T.; Drennan, C.L. Crystal structure of the non-heme iron halogenase SyrB2 in syringomycin biosynthesis. Nature 2006, 440, 368-371.
84. IV-oxo intermediate. Biochemistry 2005, 44, 3845-3855.
85. Blasiak, L.C.; Drennan, C. L. Structural perspective on enzymatic halogenation. Acc. Chem. Res. 2009, 42, 147-155.
86. Jiang, W.; Heemstra, J.R., Jr.; Forseth, R.R.; Neumann, C.S.; Manaviazar, S.; Schroeder, F.C.; Hale, K.J.; Walsh, C.T. Biosynthetic chlorination of the piperazate residue in kutzneride biosynthesis by KthP. Biochemistry 2011, 50, 6063-6072.
87. Fujimori, D.G.; Hrvatin, S.; Neumann, C.S.; Strieker, M.; Marahiel, M.A.; Walsh, C.T. Cloning and characterization oft he biosynthetic gene cluster of kutznerides. Proc. Natl. Acad. Sci. U.S.A. 2007, 104, 16498-16503.
88. Marais, J.S.C. Monofluoroacetic acid, the toxic principle of "gifblaar" Dichapetalum cymosum (Hook) Engl. Onderstepoort J. Vet. Sci. Anim. Ind., 1944, 20, 67-73.
89. Reid, K.A.; Hamilton, J.T.; Bowden, R.D.; O'Hagan, D.; Dasaradhi, L.; Amin, M.R.; Harper, D.B. Biosynthesis of secondary metabolites by Streptomyces cattleya. Microbiology 1995, 141, 1385-1393.
90. Schaffrath, C.; Cobb, S.L.; O'Hagan, D. Cell-free biosynthesis of fluoroacetate and 4-fluorothreonine in Streptomyces cattleya. Angew. Chem. Int. Ed. 2002, 41, 3913-3915.
91. O'Hagan, D. Recent developments on the fluorinase from Streptomyces cattleya. J. Fluorine Chem. 2006, 127, 1479-1483.
92. Dong, C.; Huang, F.; Deng, H.; Schaffrath, C.; Spencer, J.B.; O'Hagan, D.; Naismith, J.H. Crystal structure and mechanism of a bacterial fluorinating enzyme. Nature 2004, 427, 561-565.
93. Deng, H.; Cobb, S.L.; McEwan, A.R.; McGlinchey, R.P.; Naismith, J.H.; O'Hagan, D.; Robinson, D.A.; Spencer, J.B. The fluorinase from Streptomyces cattleya is also a chlorinase. Angew. Chem. Int. Ed. 2006, 45, 759-762.
94. Eustaquio, A.S.; Pojer, F.; Noel, J.P.; Moore, B.S. Discovery and characterization of a marine bacterial SAM-dependent chlorinase. Nat. Chem. Biol. 2008, 4, 69-74.
95. Harper, D.B. Halomethane from halide ion-a highly efficient fungal conversion of environmental significance. Nature 1985, 315, 55-57.
96. Ni, X.; Hager L.P. Expression of Batis maritima methyl chloride transferase in Escherichia coli. Proc. Natl. Acad. Sci. USA 1999, 96, 3611-3615.
97. Sanchez, C.; Zhu, L.; Brana, A.F.; Salas, A.P.; Rohr, J.; Mendez, C.; Salas, J.A. Combinatorial biosynthesis of antitumor indolocarbazole compounds. Proc. Natl. Acad. Sci. U.S.A. 2005, 102, 461-466.
98. Deb Roy, A; Grüschow, S.; Caims, N.; Goss, R.J.M. Gene expression enabling diversification of natural products: chemogenetic generation of pacidamycin analogs. J. Am. Chem. Soc. 2010, 132, 12243-12245.
99. Runguphan, W.; Qu, X.; O'Connor, S.E. Integrating carbon-halogen bond formation into medicinal plant metabolism. Nature 2010, 468, 461-464.
100. 18F-labeled sugars and nucleosides for PET. Fut. Med. Chem. 2009, 1, 865-873.