Question

Expression of genes is controlled in response to the concentration of metabolites and signaling molecules within cells. One type of control mechanism depends on the ability of some mRNA molecules to form special secondary structures that are capable of directly binding to small molecules. These structures are called riboswitches and the molecules they bind to are their ligands. Binding of an mRNA to its appropriate ligand results in a conformational change in the mRNA, and as a consequence, the transcription of this mRNA may be prematurely terminated or its translation may be inhibited. By sensing metabolite concentrations, riboswitches participate in feedback circuits. When the ligand is present at high concentrations, the riboswitch inhibits the expression of genes needed to replenish this ligand. Scientists are employing a wide range of bioinformatics, genetics, and biochemical techniques to discover, study and use riboswitches for development of novel antibiotics and therapeutics.

For this discussion forum share a thought, an idea, or an application that you found striking. Explain why (in 250-300 words). Cite your references. PLEASE TYPE.

Answer 1

A riboswitch is gene regulatory mRNA domain generally located in the 5’ end of the untranslated region, which generally responds to the concentration of verity of metabolite and second messenger molecules. Upon binding of these molecules( ligands) to the aptamer(binding site present at the riboswitch of mRNA), they modulate either transcription termination or initiation/termination of translation. a catalytic glmS riboswitch is a good example of riboswitch which is present in many Gram-positive bacteria. It is presented at the 5’ UTR of the glmS mRNA that code for fructose-6-phosphate amidotransferase which catalyzes a reaction that produces GlcN6P. This metabolic product is very important for the survival of the bacterium as this is the part of the metabolic pathway which affects the synthesis of the cell wall in the bacterium. glmS riboswitch recognizes GlcN6P and upon binding, it targetes the glmS mRNA for self-cleavage and inactivation(1). As the above example suggest a very potent role of this secondary structure of mRNA, Scientists are employing a wide range of bioinformatics, genetics, and biochemical techniques to discover, study and use riboswitches for development of novel antibiotics and therapeutics. More than 13 different distinct riboswitches 3D structure has been identified and using bioinformatics tools scientist are trying to reveal the structure of the binding groove( pocket where ligands bind). Understanding of structure of these pocket will give a wide idea of the binding pattern of the ligands. Therefore it will help the biochemist to design analog molecules that can trigger their respective riboswitch to terminate the translation of essential gene in bacteria that are very important for their survival in the host(2). Beside Riboswitch are mostly present in prokaryotes and some lower eukaryote it makes an ideal target as well. Any drug that will target this structure will have high specificity, Therefore will have less chance to hit the off target in which such drug will be administrated.

Reference:

1.Ferré-D’Amaré AR. The glmS ribozyme: use of a small molecule coenzyme by a gene-regulatory RNA.

2 Katherine E. Deigan, Adrian R. Ferré-D’Amaré: Riboswitches: discovery of drugs that target bacterial gene-regulatory RNAs