Abstract
In nature, halogenation is a strategy used to increase the biological activity of secondary metabolites, compounds that are often effective as drugs. However, halides are not particularly reactive unless they are activated, typically by oxidation. The pace of discovery of new enzymes for halogenation is increasing, revealing new metalloenzymes, flavoenzymes, S-adenosyl-L-methionine (SAM)-dependent enzymes and others that catalyse halide oxidation using dioxygen, hydrogen peroxide and hydroperoxides, or that promote nucleophilic halide addition reactions.
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References
Faulkner, D. J. Marine natural products. Nat. Prod. Rep. 19, 1–48 (2002).
Gribble, G. W. Naturally occurring organohalogen compounds. Acc. Chem. Res. 31, 141–152 (1998).
Carpenter, L. J. & Liss, P. S. On temperate sources of bromoform and other reactive bromine gases. J. Geophys. Res. 105, 20539–20547 (2002).
Hager, L. P., Morris, D. R., Brown, F. S. & Eberwein, H. Chloroperoxidase. II. Utilization of halogen anions. J. Biol. Chem. 241, 1769–1777 (1966).
Fenical, W. Halogenation in the Rhodophyta: a review. J. Phycol. 11, 245–259 (1975).
Wolinsky, L. E. & Faulkner, D. J. A biomimetic approach to the synthesis of Laurencia metabolites. Synthesis of 10-bromo-α-chamigrene. J. Org. Chem. 41, 597–600 (1976).
Manthey, J. A. & Hager, L. P. Characterization of the catalytic properties of bromoperoxidase. Biochemistry 28, 3052–3057 (1989).
Manthey, J. A. & Hager, L. P. Characterization of the oxidized states of bromoperoxidase. J. Biol. Chem. 260, 9654–9659 (1985).
Roach, M. P. et al. Notomastus lobatus chloroperoxidase and Amphitrite ornata dehaloperoxidase both contain histidine as their proximal heme iron ligand. Biochemistry 36, 2197–2202 (1997).
Vilter, H. Peroxidases from Phaeophyceae. III. Catalysis of halogenation by peroxidases from Ascophyllum nodosum (L.) Le Jol. Bot. Mar. 26, 429–435 (1983).
Vilter, H. Peroxidases from Phaeophyceae. A vanadium(v)-dependent peroxidase from Ascophyllum nodosum . Phytochemistry 23, 1387–1390 (1984).
Wever, R., Plat, H. & De Boer, E. Isolation procedure and some properties of the bromoperoxidase from the seaweed Ascophyllum nodosum . Biochim. Biophys. Acta 830, 181–186 (1985).
Vaillancourt, F. H., Yin, J. & Walsh, C. T. SyrB2 in syringomycin E biosynthesis is a nonheme FeII α-ketoglutarate- and O2-dependent halogenase. Proc. Natl Acad. Sci. USA 102, 10111–10116 (2005).
Chen, X. & van Pée, K.-H. Catalytic mechanisms, basic roles, and biotechnological and environmental significance of halogenating enzymes. Acta Biochim. Biophys. Sin. (Shanghai) 40, 183–193 (2008).
Deng, H. & O'Hagan, D. The fluorinase, the chlorinase and the duf-2 enzymes. Curr. Opin. Chem. Biol. 12, 582–592 (2008).
Wuosmaa, A. M. & Hager, L. P. Methyl chloride transferase: a carbocation route for biosynthesis of halometabolites. Science 249, 160–162 (1990).
Blasiak, L. C. & Drennan, C. L. Structural perspective on enzymatic halogenation. Acc. Chem. Res. 42, 147–155 (2009).
Wagner, C., Omari, E. M. & König, G. M. Biohalogenation: nature's way to synthesize halogenated metabolites. J. Nat. Prod. 72, 540–553 (2009).
Neumann, C. S., Fujimori, D. G. & Walsh, C. T. Halogenation strategies in natural product biosynthesis. Chem. Biol. 15, 99–109 (2008).
Fujimori, D. G. & Walsh, C. T. What's new in enzymatic halogenations. Curr. Opin. Chem. Biol. 11, 553–560 (2007).
Littlechild, J., Rodriguez, E. G. & Isupov, M. Vanadium containing bromoperoxidase — insights into the enzymatic mechanism using X-ray crystallography. J. Inorg. Biochem. 103, 617–621 (2009).
Vaillancourt, F. H., Yeh, E., Vosburg, D. A., Garneau-Tsodikova, S. & Walsh, C. T. Nature's inventory of halogenation catalysts: oxidative strategies predominate. Chem. Rev. 106, 3364–3378 (2006). This review summarizes the halogenating enzymes with particular insight into the Fe NH –αKG halogenases.
Butler, A. & Carter-Franklin, J. N. A role for vanadium bromoperoxidase in the biosynthesis of halogenated marine natural products. Nat. Prod. Rep. 21, 180–188 (2004).
Sundaramoorthy, M., Terner, J. & Poulos, T. L. The crystal structure of chloroperoxidase: a heme peroxidase–cytochrome P450 functional hybrid. Structure 3, 1367–1378 (1995).
Kuhnel, K., Blankenfeldt, W., Terner, J. & Schlinchting, I. Crystal structures of chloroperoxidase with its bound substrates and complexed with formate, acetate and nitrate. J. Biol. Chem. 281, 23990–23998 (2006).
Wagenknecht, H.-A. & Wolf-Dietrich, W. Identification of intermediates in the catalytic cycle of chloroperoxidase. Chem. Biol. 4, 367–372 (1997).
Libby, R. D., Beachy, T. M. & Phipps, A. K. Quantitating direct chlorine transfer from enzyme to substrate in chloroperoxidase-catalyzed reactions. J. Biol. Chem. 271, 21820–21827 (1996).
Reddy, C. M. et al. A chlorine isotope effect for enzyme-catalyzed chlorination. J. Am. Chem. Soc. 124, 14526–14527 (2002). This paper established 35Cl/37Cl isotope fractionation for the first time in a haloperoxidase during turnover.
Van Schijndel, J. W. P. M., Vollenbroek, E. G. M. & Wever, R. The chloroperoxidase from the fungus Curvularia inaequalis: a novel vanadium enzyme. Biochim. Biophys. Acta 1161, 249–256 (1993).
Winter, J. M. et al. Molecular basis for chloronium-mediated meroterpene cyclization. Cloning, sequencing, and heterologous expression of the napyradiomycin biosynthetic gene cluster. J. Biol. Chem. 282, 16362–16368 (2007).
Küpper, F. C. et al. Iodide accumulation provides kelp with an inorganic antioxidant impacting atmospheric chemistry. Proc. Natl Acad. Sci. USA 105, 6954–6958 (2008).
Ortiz-Bermudez, P. et al. Chlorination of lignin by ubiquitous fungi has a likely role in global organochlorine production. Proc. Natl Acad. Sci. USA 104, 3895–3900 (2007).
Weyand, M. et al. X-ray structure determination of a vanadium-dependent haloperoxidase from Ascophyllum nodosum at 2.0 Å resolution. J. Mol. Biol. 293, 595–611 (1999).
Isupov, M. N. et al. Crystal structure of dodecameric vanadium-dependent bromoperoxidase from the red algae Corallina officinalis . J. Mol. Biol. 299, 1035–1049 (2000).
Messerschmidt, A. & Wever, R. X-ray structure of a vanadium containing enzyme: chloroperoxidase from the fungus Curvularia inaequalis . Proc. Natl Acad. Sci. USA 93, 392–396 (1996).
Colpas, G. J., Hamstra, B. J., Kampf, J. W. & Pecoraro, V. L. Functional models for vanadium haloperoxidases: reactivity and mechanism of halide oxidation. J. Am. Chem. Soc. 118, 3469–3478 (1996).
Hemrika, W., Rokus, R., Macedo-Ribeiro, S., Messerschmidt, A. & Wever, R. Heterologous expression of the vanadium-containing chloroperoxidases from Curvularia inaequalis in Saccharomyces cerevisiae and site-directed mutagenesis of the active site residues His496, Lys353, Arg360, and Arg490 . J. Biol. Chem. 274, 23820–23827 (1999).
Everett, R. R., Kanofsky, J. R. & Butler, A. Mechanism of dioxygen formation catalyzed by vanadium bromoperoxidase. Steady state kinetic analysis and comparison to the mechanism of bromination. J. Biol. Chem. 265, 15671–15679 (1990).
Tschirret-Guth, R. A. & Butler, A. Evidence for organic substrate binding to vanadium bromoperoxidase. J. Am. Chem. Soc. 116, 411–412 (1994).
Carter-Franklin, J. N., Parrish, J. D., Tschirret-Guth, R. A., Little, R. D. & Butler, A. Vanadium haloperoxidase-catalyzed bromination and cyclization of terpenes. J. Am. Chem. Soc. 125, 3688–3689 (2003).
Carter-Franklin, J. N. & Butler, A. Vanadium bromoperoxidase-catalyzed biosynthesis of halogenated marine natural products. J. Am. Chem. Soc. 126, 15060–15066 (2004). This paper shows diasteroselectivity of a V-BPO-catalysed reaction for the first time in the bromination and cyclization of the terpene ( E )-(+)-nerolidol.
Wang, Y. J., Huang, J. J. & Leadbetter, J. R. Acyl-HSL signal decay: intrinsic to bacterial cell-cell communications. Adv. Appl. Microbiol. 61, 27–58 (2007).
Steinberg, P. D., de Nys, R. & Kjelleberg, S. in Marine Chemical Ecology (eds McClintock, J. B. & Baker, B. J.) 355–387 (CRC, 2001).
Borchardt, S. A. et al. Reaction of acylated homoserine lactone bacterial signaling molecules with oxidized halogen antimicrobials. Appl. Environ. Microbiol. 67, 3174–3179 (2001).
Blasiak, L. C., Vaillancourt, F. H., Walsh, C. T. & Drennan, C. L. Crystal structure of the non-haem iron halogenase SyrB2 in syringomycin biosynthesis. Nature 440, 368–371 (2006).
Hanauske-Abel, H. M. & Popowicz, A. M. The HAG mechanism: a molecular rationale for the therapeutic application of iron chelators in human diseases involving the 2-oxoacid utilizing dioxygenases. Curr. Med. Chem. 10, 1005–1019 (2003).
Matthews, M. L. et al. Substrate-triggered formation and remarkable stability of the C–H bond-cleaving chloroferryl intermediate in the aliphatic halogenase, SyrB2. Biochemistry 48, 4331–4343 (2009). This paper provides significant mechanistic insight into the reactions catalysed by the Fe NH –αKG halogenases in comparison with those catalysed by the Fe NH –αKG oxygenases.
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. Am. Chem. Soc. 128, 3900 (2006).
Chang, Z. et al. 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 296, 235–247 (2002).
Ueki, M. et al. Enzymatic generation of the antimetabolite γ, γ-dichloroaminobutyrate by NRPS and mononuclear iron halogenase action in a streptomycete. Chem. Biol. 13, 1183–1191 (2006).
Vaillancourt, F. H., Yeh, E., Vosburg, D. A., O'Connor, S. E. & Walsh, C. T. Cryptic chlorination by a non-haem iron enzyme during cyclopropyl amino acid biosynthesis. Nature 436, 1191–1194 (2005). This paper is the first report of cyclopropyl formation via a chlorinated precursor.
Chang, Z. et al. Biosynthetic pathway and gene cluster analysis of curacin A, an antitubulin natural product from the tropical marine cyanobacterium Lyngbya majuscula . J. Nat. Prod. 67, 1356–1367 (2004).
Edwards, D. J. et al. Structure and biosynthesis of the jamaicamides, new mixed polyketide-peptide neurotoxins from the marine cyanobacterium Lyngbya majuscula . Chem. Biol. 11, 817–833 (2004).
Gu, L. et al. Metamorphic enzyme assembly in polyketide diversification. Nature 459, 731–735 (2009). This paper demonstrates coevolution of enzymes for metabolic diversification in the biosynthetic pathways leading to β -branched cyclopropane in curacin A and a vinyl chloride in jamaicamide A.
Ni, X. & Hager, L. P. cDNA cloning of Batis maritima methyl chloride transferase and purification of the enzyme. Proc. Natl Acad. Sci. USA 95, 12866–12871 (1998).
Eustaquio, A. S., Pojer, F., Noe, J. P. & Moore, B. S. Discovery and characterization of a marine bacterial SAM-dependent chlorinase. Nature Chem. Biol. 4, 69–74 (2008).
Dong, C. et al. Crystal structure and mechanism of a bacterial fluorinating enzyme. Nature 427, 561–565 (2004).
Deng, H. et al. The fluorinase from Streptomyces cattleya is also a chlorinase. Angew. Chem. Int. Ed. 45, 759–762 (2006).
Cadicamo, C. D., Courtieu, J., Deng, H., Meddour, A. & O'Hagan, D. Enzymatic fluorination in Streptomyces cattleya takes place with an inversion of configuration consistent with an SN2 reaction mechanism. ChemBioChem 5, 685–690 (2004).
Michels, J. J., Allain, E. J., Borchardt, S. A., Hu, P. & McCoy, W. F. Degradation pathway of homoserine lactone bacterial signal molecules by halogen antimicrobials identified by liquid chromatography with photodiode array and mass spectrometric detection. J. Chromatogr. A 898, 153–165 (2000).
Acknowledgements
A.B. greatly acknowledges US National Science Foundation Division of Chemistry award number 0719553 for support of her research.
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Correspondence should be addressed to A.B. (butler@chem.ucsb.edu).
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Butler, A., Sandy, M. Mechanistic considerations of halogenating enzymes. Nature 460, 848–854 (2009). https://doi.org/10.1038/nature08303
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DOI: https://doi.org/10.1038/nature08303
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