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

SyrB2 in syringomycin E biosynthesis is a nonheme Fe II α-ketoglutarate- and O 2 -dependent halogenase

“…This type of reaction may be the chemical niche for nonheme Fe II halogenases. It is very likely that a second example of this nonheme Fe II halogenase class is the BarbB1͞B2 pair, implicated in functionalizing the unactivated methyl group of a L-Leu moiety during trichloroleucine formation as a building block in barbamide biosynthesis (8). Thus, a subclass of the nonheme Fe II ␣-KG-dependent superfamily may use ␣-KG and O 2 to generate high-valent oxoiron species but divert them for halogenation, rather than hydroxylation, of many unactivated carbon centers in the Ͼ4,000 chlorinated and brominated natural products.…”

“…There are also aliphatic carbons bearing one, two, or three chlorine atoms in natural products, such as the 4-Cl-L-Thr at residue nine of the peptide scaffold of the phytotoxic syringomycin E from Pseudomonas syringae pv. syringae B301D (6), the dichlorinated ␤-hydroxy acid of lyngbyabellin A (7), and the trichloroleucine-derived moiety in barbamide (8) (Fig. 1B).…”

“…For example, neither the barbamide synthetase assembly line gene cluster nor the syringomycin synthetase cluster (6,8) contain obvious flavoprotein halogenase homologs. Instead, they have ORFs predicted to be nonheme Fe II , ␣-ketoglutarate (␣-KG)-requiring enzymes.…”

Biosynthesis and function of polyacetylenes and allied natural products

“…The timing and mechanism of both the alkene chlorination and alkyne bromination steps have not yet been defined. A good candidate for the chlorinating agent is JamE, whose sequence homology to the phytanoyl-CoA dioxygenase family aligns it with related enzymes involved in marine halogenated NRPS and PK-NRPS products (barbamide and syringomycin) [230,231]. Extension of the linear precursor continues during modules 2-8 with C-and O-methyltransferases located in modules 2 and 6, respectively.…”

“…46) [416]. It remains to be determined whether these compounds are produced using isopropyl halogenation chemistry common to barbamide [230] and herbacic acid [417] followed by demethylation or, alternatively, through repetitive chlorination of methyl termini on linear alkanes. A putative precursor to these compounds, 6-acetamidotridecane, was purified in the same study.…”