Elucidating the biosynthetic pathway of valclavam Katsiaryna Usachova and Barrie Wilkinson John Innes Centre, UK
Clavams are natural products with a core β-lactam and oxazolidine fused ring structure, or an oxapenam. Clavulanic acid ( 1 ) is a clavam β-lactamase inhibitor 1 commonly prescribed against bacterial infections, in combination with the β-lactam amoxicillin. The inhibitory activity of 1 is believed to lie largely in its distinctive 5R stereochemistry 2 . This differentiates 1 from the related 5S clavam family, members of which are known to inhibit methionine biosynthesis and have antifungal properties 3,4,5 . Curiously, the biosynthesis of 1 in the industrial producer Streptomyces clavuligerus shares its early steps and regulation with the pathways for production of 5S clavam natural products 6 . This cross-talk between biosynthetic pathways has hindered characterisation and optimisation of clavulanic acid production. In contrast, Streptomyces antibioticus Tü1718 has a much simpler profile consisting solely of 5S clavam metabolites, namely valclavam ( 2 ) and 2‑hydroxyethylclavam ( 3 ) 7,8 . We have performed genetic characterisation of the putative late step genes involved in the biosynthesis of 2 and 3 from clavaminic acid ( 4 ), the common precursor of both 5R and 5S clavams. Work is in progress to determine chemical structures of late step intermediates in the biosynthetic pathway, as well as putative reaction mechanisms taking place.
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