A REVIEW New frontiers in biological halogenation

1. SUMMARYThe synthesis of halogenated compounds in biologicalsystems is well established, yet the mechanisms by whichthese compounds are formed are poorly understood. Manycommercially important compounds, such as pharmaceuti-cals and agrochemicals, contain halogens; indeed somehalogenated natural products, such as the antibiotic vanco-mycin, are themselves valuable. Furthermore, several envi-ronmentally significant organohalogens can be formednaturally, for example it is likely that a significant proportionof the atmospheric bromomethane is produced by higherplants (Gan et al. 1998).While chemical synthesis of organohalogens can bedifficult, the biological production of these compoundsoccurs under relatively mild conditions and often with agreater degree of specificity. Therefore an understanding ofthe biosynthesis of halometabolites, and in particular, theenzymology of carbon–halogen bond formation, may pro-vide convenient biotechnological methods for the halogen-ation of organic compounds. For over 30 yearshaloperoxidases were the only halogenating enzymes thathad been identified and it was largely accepted that theseenzymes were responsible for almost all biological halogen-ation reactions. However, in recent years evidence hasaccumulated pointing to the existence of other halogenasesand now the nature of these enzymes is being revealed. Thisreview concentrates on the occurrence, mechanism andbiocatalytic potential of the halogenating enzymes that arecurrently known.2. HALOMETABOLITESThe first report of a halogen-containing natural product(halometabolite) was that of the iodinated amino aciddiiodotyrosine (Fig. 1) from the coral Gorgonia cavolii in thelate nineteenth century (Drechsel 1896). For many years suchcompounds were considered rare and of little biologicalsignificance and there is still a perception that organohalogenspresent in the environment are of anthropogenic origin only.However,evenwell-knownpollutantssuchaspolychlorinateddibenzo-p-dioxins and dibenzofurans (PCDD/PCDF), ap-pear to be also formed naturally (Hoekstra et al. 1999).Currently there are over 3600 halogenated natural productsknown, from bacteria, fungi, algae, higher plants and animals.Examples of halometabolites are shown in Fig. 1, but for acomprehensive review of the structural diversity of thesecompounds the reader is directed to Gribble (1998). Chloro-metabolites and bromometabolites predominate; iodinatedand fluorinated natural products are much less common. Thefunctions of halometabolites are varied and they can havedistinct physiological or biochemical roles, for example thelone star tick uses 2,6-dichlorophenol as a sex-pheromone(Berger 1972), while 4-chloroindolyl-3-acetic acid is a plantgrowth hormone (Marumo et al. 1968). Several halometab-olites, particularly those of marine origin, appear to have adefensiverole(Gribble1999)andanumberofhalometabolitesisolated from bacteria and fungi have antibiotic activity, forexample chloramphenicol and chlortetracycline. Theassumed role of many bacterial halometabolites conferringan advantage on the producer by inhibiting the growth ofcompeting organisms has been questioned, as these com-pounds are usually produced in extremely small quantities innature (van Pe´e 1996). Nevertheless, their biosynthesis1. Summary, 5392. Halometabolites, 5393. Halogenating enzymes, 5403.1 Haloperoxidases, 5403.2 FADH