Simple rules govern the diversity of bacterial nicotianamine-like metallophores
2019
In metal-scarce environments, some pathogenic bacteria produce opine-type metallophores mainly to face the host9s nutritional immunity. This is the case of staphylopine, pseudopaline and yersinopine, identified in
Staphylococcus aureus
,
Pseudomonas aeruginosa and
Yersinia pestis
respectively. Depending on the species, these metallophores are synthesized by two (CntLM) or three enzymes (CntKLM), CntM catalyzing the last step of biosynthesis using diverse substrates (pyruvate or α-ketoglutarate), pathway intermediates (xNA or yNA) and cofactors (NADH or NADPH). Here, we explored substrate specificity of CntM by combining bioinformatics and structural analysis with chemical synthesis and enzymatic studies. We found that NAD(P)H selectivity was mainly due to the amino acid at position 33 (
S. aureus numbering) which ensures a preferential binding to NADPH when it is an arginine. Moreover, whereas CntM from
P. aeruginosa
preferentially uses yNA over xNA, the staphylococcal enzyme is not stereospecific. Most importantly, selectivity towards α-ketoacids is largely governed by a single residue at position 150 of CntM (
S. aureus numbering): an aspartate at this position ensures selectivity towards pyruvate whereas an alanine leads to the consumption of both pyruvate and α-ketoglutarate. Modifying this residue in
P. aeruginosa led to a complete reversal of selectivity. Thus, opine-type metallophore diversity is governed by the absence/presence of a
cntK gene encoding a histidine racemase, and the amino acid residue at position 150 of CntM. These two simple rules predict the production of a fourth metallophore by
Paenibacillus mucilaginosus
, which was confirmed
in vitro and called bacillopaline.
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