Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0162871 (abdominal aortic aneurysm)
8,664 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Ribozymes use divalent cations for structural stabilization, as catalytic cofactors, or both. Because of the prominent role of Ca²⁺ in intracellular signaling, engineered ribozymes with stringent Ca²⁺ selectivity would be important in biotechnology. The wild-type glmS ribozyme (glmS^WT) requires glucosamine-6-phosphate (GlcN6P) as a catalytic cofactor. Previously, a glmS ribozyme variant with three adenosine mutations (glmS^AAA) was identified, which dispenses with GlcN6P and instead uses, with little selectivity, divalent cations as cofactors for site-specific RNA cleavage. We now report a Ca²⁺-specific ribozyme (glmS^Ca) evolved from glmS^AAA that is >10,000 times more active in Ca²⁺ than Mg²⁺, is inactive in even 100 mM Mg²⁺, and is not responsive to GlcN6P. This stringent selectivity, reminiscent of the protein nuclease from Staphylococcus, allows rapid and selective ribozyme inactivation using a Ca²⁺ chelator such as EGTA. Because glmS^Ca functions in physiologically relevant Ca²⁺ concentrations, it can form the basis for intracellular sensors that couple Ca²⁺ levels to RNA cleavage. Biochemical analysis of glmS^Ca reveals that it has co-opted for selective Ca²⁺ binding a nonspecific cation-binding site responsible for structural stabilization in glmS^WT and glmS^AAA Fine-tuning of the selectivity of the cation site allows repurposing of this preexisting molecular feature.
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PMID:A divalent cation-dependent variant of the glmS ribozyme with stringent Ca²⁺ selectivity co-opts a preexisting nonspecific metal ion-binding site. 2793 87

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