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A disconnect between high-affinity binding and efficient regulation by antifolates and purines in the tetrahydrofolate riboswitch.

ABSTRACT: The tetrahydrofolate (THF) riboswitch regulates folate transport and metabolism in a number of Firmicutes by cooperatively binding two molecules of THF. To further understand this riboswitch's specificity for THF, binding and regulatory activity of a series of THF analogs and antifolates were examined. Our data reveal that although binding is dominated by the RNA's interactions with the pterin moiety, the para-aminobenzoic acid (pABA) moiety plays a significant role in transcriptional regulation. Further, we find that adenine and several other analogs bind with high affinity by an alternative binding mechanism. Despite a similar affinity to THF, adenine is a poor regulator of transcriptional attenuation. These results demonstrate that binding alone does not determine a compound's effectiveness in regulating the activity of the riboswitch-a complication in current efforts to develop antimicrobials that target these RNAs.

SUBMITTER: Trausch JJ

PROVIDER: S-EPMC3935398 | biostudies-literature | 2014 Feb

REPOSITORIES: biostudies-literature

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A disconnect between high-affinity binding and efficient regulation by antifolates and purines in the tetrahydrofolate riboswitch.

Trausch Jeremiah J JJ Batey Robert T RT

Chemistry & biology 20140102 2

The tetrahydrofolate (THF) riboswitch regulates folate transport and metabolism in a number of Firmicutes by cooperatively binding two molecules of THF. To further understand this riboswitch's specificity for THF, binding and regulatory activity of a series of THF analogs and antifolates were examined. Our data reveal that although binding is dominated by the RNA's interactions with the pterin moiety, the para-aminobenzoic acid (pABA) moiety plays a significant role in transcriptional regulation ...[more]

PMID: 24388757

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