Eucolona M. Toci, Ananya Majumdar, Caren L. Freel Meyers
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Aldehyde‐based activation of C2α‐lactylthiamin diphosphate decarboxylation on bacterial 1‐deoxy‐d‐xylulose 5‐phosphate synthase.
1‐Deoxy‐d‐xylulose 5‐phosphate synthase (DXPS) catalyzes the thiamin diphosphate (ThDP)‐dependent formation of DXP from pyruvate (donor substrate) and d‐glyceraldehyde 3‐phosphate (d‐GAP, acceptor substrate) in bacterial central metabolism. DXPS uses a ligand‐gated mechanism in which binding of a small molecule “trigger” activates the first enzyme‐bound intermediate, C2α‐lactylThDP (LThDP), to form the reactive carbanion via LThDP decarboxylation. d‐GAP is the natural acceptor substrate for DXPS and also serves a role as a trigger to induce LThDP decarboxylation in the gated step. Additionally, we have shown that O2 and d‐glyceraldehyde (d‐GA) can induce LThDP decarboxylation. We hypothesize this ligand‐gated mechanism poises DXPS to sense and respond to cellular cues in metabolic remodeling during bacterial adaptation. Here we sought to characterize features of small molecule inducers of LThDP decarboxylation. Using a combination of CD, NMR and biochemical methods, we demonstrate that the α‐hydroxy aldehyde moiety of d‐GAP is sufficient to induce LThDP decarboxylation en route to DXP formation. A variety of aliphatic aldehydes also induce LThDP decarboxylation. The study highlights the capacity of DXPS to respond to different molecular cues, lending support to potential multifunctionality of DXPS and its metabolic regulation by this mechanism.
期刊介绍:
ChemBioChem (Impact Factor 2018: 2.641) publishes important breakthroughs across all areas at the interface of chemistry and biology, including the fields of chemical biology, bioorganic chemistry, bioinorganic chemistry, synthetic biology, biocatalysis, bionanotechnology, and biomaterials. It is published on behalf of Chemistry Europe, an association of 16 European chemical societies, and supported by the Asian Chemical Editorial Society (ACES).