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Structure-guided discovery of the metabolite carboxy-SAM that modulates tRNA function.

<div class='caption-title'>Proposed chemical mechanism for the biosynthesis of cmo5U</div>
<div class='caption-title'>Structure of the CmoA:Cx-SAM complex</div>
<div class='caption-title'>Identification of low molecular weight compounds associated with CmoA-mediated Cx-SAM production</div>
Kim J, Xiao H, Bonanno JB, Kalyanaraman C, Brown S, Tang X, Al-Obaidi NF, Patskovsky Y, Babbitt PC, Jacobson MP, Lee YS, Almo SC
OpenAccess logo Nature 498 123-6 (2013)
Cited: 51 times
EuropePMC logo PMID: 23676670

Abstract

The identification of novel metabolites and the characterization of their biological functions are major challenges in biology. X-ray crystallography can reveal unanticipated ligands that persist through purification and crystallization. These adventitious protein-ligand complexes provide insights into new activities, pathways and regulatory mechanisms. We describe a new metabolite, carboxy-S-adenosyl-l-methionine (Cx-SAM), its biosynthetic pathway and its role in transfer RNA modification. The structure of CmoA, a member of the SAM-dependent methyltransferase superfamily, revealed a ligand consistent with Cx-SAM in the catalytic site. Mechanistic analyses showed an unprecedented role for prephenate as the carboxyl donor and the involvement of a unique ylide intermediate as the carboxyl acceptor in the CmoA-mediated conversion of SAM to Cx-SAM. A second member of the SAM-dependent methyltransferase superfamily, CmoB, recognizes Cx-SAM and acts as a carboxymethyltransferase to convert 5-hydroxyuridine into 5-oxyacetyl uridine at the wobble position of multiple tRNAs in Gram-negative bacteria, resulting in expanded codon-recognition properties. CmoA and CmoB represent the first documented synthase and transferase for Cx-SAM. These findings reveal new functional diversity in the SAM-dependent methyltransferase superfamily and expand the metabolic and biological contributions of SAM-based biochemistry. These discoveries highlight the value of structural genomics approaches in identifying ligands within the context of their physiologically relevant macromolecular binding partners, and in revealing their functions.

Reviews - 4gek mentioned but not cited (1)

  1. S-Adenosylmethionine: more than just a methyl donor. Lee YH, Ren D, Jeon B, Liu HW. Nat Prod Rep 40 1521-1549 (2023)

Articles - 4gek mentioned but not cited (5)

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Reviews citing this publication (11)

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