Carboxylic Acid Tailoring in Thioquinolobactin Biosynthesis

The
biosynthetic mechanism underlying the formation of thiocarboxylic
acid moieties in natural products remains largely unknown. Thioquinolobactin
(TQB) is a Pseudomonas fluorescens derived siderophore
that contains a thiocarboxylic acid moiety within its structure. Although
the biosynthetic gene cluster and proposed pathway for TQB formation
have been reported, the biosynthetic mechanism related to the thiocarboxylic
acid formation are yet to be fully understood. In this study, we address
this question by demonstrating that a unique dual-domain protein QbsL,
which possesses both CoA ligase and methyltransferase activities,
along with the sulfurtransferase QbsK, facilitates the assembly of
the thiocarboxylic acid. Based on this mechanism, we develop a chemoenzymatic
method to convert carboxylic acid into selenocarboxylic acid, thereby
generating selenium-containing analogues of TQB. These findings resolve
the long-standing mystery in TQB biosynthesis and expand the synthetic
toolkit for carboxylic acid modification.