The desABCD operon is proposed to encode for desferrioxamine siderophore biosynthesis. This siderophore class includes desferrioxamine B, a common frontline therapeutic for the treatment of iron overload. In the case of the macrocyclic siderophore, desferrioxamine E, DesA-C converts L-lysine to N,N-hydroxy-succinyl-cadaverine (HSC), after which DesD, a nonribosomal peptide synthetase (NRPS)-independent siderophore synthetase (NIS), catalyzes the ATP-dependent trimerization and macrocyclization of three HSC units to generate desferrioxamine E. However, the currently accepted biosynthetic model does not fully account for the diverse structures within the desferrioxamine class of natural products. Herein, we establish a new paradigm for desferrioxamine siderophore biosynthesis in which DesD facilitates substrate-templated oligomerization to control product outcome. We report multiple X-ray crystal structures of DesD in functionally relevant states that reveal the orientation of substrates in the adenylation and condensation sites. The synthesis and biochemical investigation of rationally designed substrates and inhibitors, including a hydrolytically stable 5’-O-sulfamoyl-adenoside acyl adenylate analogue, will be discussed to support our novel mechanistic proposal for desferrioxamine biosynthesis.

Structure, mechanism, and inhibition of the NIS siderophore synthetase DesD

ACS Spring Meeting 2021

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