title: Thiamine derivatives bind messenger RNAs directly to regulate bacterial gene expression.
abstract: Although proteins fulfil most of the requirements that biology has for structural and functional components such as enzymes and receptors, RNA can also serve in these capacities. For example, RNA has sufficient structural plasticity to form ribozyme and receptor elements that exhibit considerable enzymatic power and binding specificity. Moreover, these activities can be combined to create allosteric ribozymes that are modulated by effector molecules. It has also been proposed that certain messenger RNAs might use allosteric mechanisms to mediate regulatory responses depending on specific metabolites. We report here that mRNAs encoding enzymes involved in thiamine (vitamin B(1)) biosynthesis in Escherichia coli can bind thiamine or its pyrophosphate derivative without the need for protein cofactors. The mRNA-effector complex adopts a distinct structure that sequesters the ribosome-binding site and leads to a reduction in gene expression. This metabolite-sensing regulatory system provides an example of a 'riboswitch' whose evolutionary origin might pre-date the emergence of proteins.
authors.affiliation: Department of Molecular, Cellular and Developmental Biology, Yale University, PO Box 208103, New Haven, Connecticut 06520-8103, USA.
authors.forename: Wade
authors.initials: W
authors.lastname: Winkler
authors.forename: Ali
authors.initials: A
authors.lastname: Nahvi
authors.forename: Ronald R
authors.initials: RR
authors.lastname: Breaker
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects; D000495:Allosteric Site / Q000187:drug effects; D001426:Bacterial Proteins / Q000235:genetics; D001483:Base Sequence; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism; D004926:Escherichia coli / Q000187:drug effects / Q000235:genetics*; D029968:Escherichia coli Proteins / Q000235:genetics; D015964:Gene Expression Regulation, Bacterial / Q000187:drug effects; D005798:Genes, Bacterial / Q000235:genetics; D008969:Molecular Sequence Data; D009154:Mutation; D009690:Nucleic Acid Conformation; D014176:Protein Biosynthesis / Q000187:drug effects; D012329:RNA, Bacterial / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D017476:Receptors, Neuropeptide Y / Q000235:genetics / Q000378:metabolism; D038621:Regulatory Sequences, Ribonucleic Acid / Q000235:genetics; D012270:Ribosomes / Q000187:drug effects / Q000378:metabolism; D013379:Substrate Specificity; D013831:Thiamine / Q000031:analogs & derivatives* / Q000096:biosynthesis / Q000378:metabolism* / Q000494:pharmacology; D013835:Thiamine Pyrophosphate / Q000378:metabolism / Q000494:pharmacology
chemical_list: D001426:Bacterial Proteins; D029742:Caenorhabditis elegans Proteins; D029968:Escherichia coli Proteins; C468272:NPR-1 protein, C elegans; D012329:RNA, Bacterial; D012333:RNA, Messenger; D017476:Receptors, Neuropeptide Y; D038621:Regulatory Sequences, Ribonucleic Acid; C105797:ThiC protein, Bacteria; D013835:Thiamine Pyrophosphate; D013831:Thiamine