Rongfeng Li, Michael S Lichstrahl, Trevor A Zandi, Lukas Kahlert, Craig A Townsend
Non-ribosomal peptide synthetases (NRPSs) assemble metabolites of medicinal and commercial value. Both serine and threonine figure prominently in these processes and separately can be converted to the additional NRPS building blocks 2,3-diaminopropionate (Dap) and 2,3-diaminobutyrate (Dab). Here we bring extensive bioinformatics, and experimentation to compose a unified view of the biosynthesis of these widely distributed non-canonical amino acids that both derive by pyridoxal-mediated β-elimination of the activated -phosphorylated substrates followed by β-addition of an amine donor. By examining monobactam biosynthesis in and in species where it is silent, we show that (2,3)-Dab synthesis depends on an l-threonine kinase (DabA), a β-replacement reaction with l-aspartate (DabB) and an argininosuccinate lyase-like protein (DabC). The growing clinical importance of monobactams to both withstand Ambler Class B metallo-β-lactamases and retain their antibiotic activity make reprogrammed precursor and NRPS synthesis of modified monobactams a feasible and attractive goal.
