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Simple rules govern the diversity of bacterial nicotianamine-like metallophores

Abstract : In metal-scarce environments, some pathogenic bacteria produce opine-type metallophores mainly to face the host's 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 $\alpha$-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 $\alpha$- 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 $\alpha$-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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Submitted on : Tuesday, September 3, 2019 - 4:07:16 PM
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Clémentine Laffont, Catherine Brutesco, Christine Hajjar, Gregorio Cullia, Roberto Fanelli, et al.. Simple rules govern the diversity of bacterial nicotianamine-like metallophores. Biochemical Journal, Portland Press, 2019, 476 (15), pp.2221-2233. ⟨10.1042/bcj20190384⟩. ⟨cea-02275929⟩



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