Dichlorination and Bromination of a Threonyl-S-Carrier Protein by the Non-heme Fe II Halogenase SyrB2

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Chemistry (HMC)

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Biosynthetic tailoring of nonribosomal peptide and polyketide natural products can enhance their biological activities. Tailoring enzymes can introduce alkyl, acyl, or glycosyl groups onto natural product scaffolds and can oxidize or halogenate biosynthetic intermediates. Chlorinated and brominated molecules make up more than 95 % of the more than 4500 known halogenated metabolites. Chloro and bromo substituents are frequently found on aromatic and heteroaromatic rings, and many terpene scaffolds are also brominated and chlorinated by marine microorganisms. Halogenating enzymes discovered to date fall into two categories based on their utilization either of hydrogen peroxide (haloperoxidases) or molecular oxygen (halogenases) as required oxidants. Haloperoxidases can contain either heme iron or a vanadate cofactor, thought to generate enzyme-bound hapohalite equivalents as proximal OCl or OBr. The O2-utilizing halogenases are typically found embedded in biosynthetic gene clusters; this suggests a tailoring role in specific natural product assembly. This second class of enzymes uses either FADH2 or non-heme FeII to activate chloride or bromide oxidatively. The flavoproteins work on electron-rich aromatic and heteroaromatic substrates.

The FeII halogenases represent a new branch of the O2 and α-ketoglutarate-decarboxylating superfamily and are powerful enough to halogenate unactivated carbon centers on aminoacyl groups tethered to nonribosomal peptide synthetase assembly lines. Thus, the 4-Cl-L-Thr residue in the phytotoxic lipodepsipeptide syringomycin E (1) is generated by the non-heme FeII halogenase SyrB2 (Scheme 1). Chlorination occurs on the threonyl skeleton only while it is linked via a thioester to a peptidyl carrier protein domain. Remarkably, the cyclopropane ring in the amino acid coronamic acid arises by a similar γ-chlorination of an L-allo-Ile-S-protein by the halogenase CmaB. The γ-chloride is then displaced intramolecularly by a thioester enolate by action of CmaC. Therefore, the CmaB-mediated chlorination is cryptic in cyclopropane formation.

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© 2006 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim