Activation of the <i>glmS</i> Ribozyme Confers Bacterial Growth Inhibition

Schüller, Anna; Matzner, Daniel; Lünse, Christina E.; Wittmann, Valentin; Schumacher, Catherine; Unsleber, Sandra; Brötz‐Oesterhelt, Heike; Mayer, Christoph; Bierbaum, Gabriele; Mayer, Günter

doi:10.1002/cbic.201600491

Cited by 24 publications

(40 citation statements)

References 45 publications

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“…S. aureus growth is inhibited by disrupting either the uptake or catabolism [11], or the de novo biosynthesis of the cell wall precursor glucosamine-6-phosphate [10,12]. S. aureus growth is inhibited by disrupting either the uptake or catabolism [11], or the de novo biosynthesis of the cell wall precursor glucosamine-6-phosphate [10,12].…”

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confidence: 99%

Functional and solution structure studies of amino sugar deacetylase and deaminase enzymes from Staphylococcus aureus

et al. 2018

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N‐Acetylglucosamine‐6‐phosphate deacetylase (NagA) and glucosamine‐6‐phosphate deaminase (NagB) are branch point enzymes that direct amino sugars into different pathways. For Staphylococcus aureus NagA, analytical ultracentrifugation and small‐angle X‐ray scattering data demonstrate that it is an asymmetric dimer in solution. Initial rate experiments show hysteresis, which may be related to pathway regulation, and kinetic parameters similar to other bacterial isozymes. The enzyme binds two Zn2+ ions and is not substrate inhibited, unlike the Escherichia coli isozyme. S. aureus NagB adopts a novel dimeric structure in solution and shows kinetic parameters comparable to other Gram‐positive isozymes. In summary, these functional data and solution structures are of use for understanding amino sugar metabolism in S. aureus, and will inform the design of inhibitory molecules.

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Functional and solution structure studies of amino sugar deacetylase and deaminase enzymes from Staphylococcus aureus

et al. 2018

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“…The glmS riboswitch regulates the expression of glucosamine-6phosphate synthase (GlmS), an enzyme that catalyzes synthesis of the essential bacterial cell wall precursor, glucosamine 6phosphate (GlcN6P) (7). Understandably, this riboswitch has become a target for antibiotic development (8,9). Unique among the known riboswitches, the glmS riboswitch functions as a self-cleaving ribozyme activated by its ligand, GlcN6P, which also serves as a catalytic cofactor for the cleavage reaction (10,11).…”

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Self-cleavage of the glmS ribozyme core is controlled by a fragile folding element

Savinov

Block

2018

Proc. Natl. Acad. Sci. U.S.A.

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Riboswitches modulate gene expression in response to small-molecule ligands. Switching is generally thought to occur via the stabilization of a specific RNA structure conferred by binding the cognate ligand. However, it is unclear whether any such stabilization occurs for riboswitches whose ligands also play functional roles, such as the glmS ribozyme riboswitch, which undergoes self-cleavage using its regulatory ligand, glucosamine 6-phosphate, as a catalytic cofactor. To address this question, it is necessary to determine both the conformational ensemble and its ligand dependence. We used optical tweezers to measure folding dynamics and cleavage rates for the core glmS ribozyme over a range of forces and ligand conditions. We found that the folding of a specific structural element, the P2.2 duplex, controls active-site formation and catalysis. However, the folded state is only weakly stable, regardless of cofactor concentration, supplying a clear exception to the ligand-based stabilization model of riboswitch function.

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“…In a recent example, Ferrier rearrangement was used for the synthesis of fluoro‐carba analogues of glucosamine‐6‐phosphate (GlcN6P) ( 19a ; Figure A), the natural glmS ribozyme ligand . GlmS ribozyme is a gene‐regulating riboswitch that controls cell wall synthesis and is present in several human pathogenic bacteria . It uses GlcN6P as a cofactor to induce catalytic self‐cleavage with a unique mechanism, not shared by other riboswitches.…”

Section: Endocyclic Oxygen Replacementmentioning

confidence: 99%

Design and synthesis of glycomimetics: Recent advances

Tamburrini

Colombo

Bernardi

2019

Medicinal Research Reviews

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In the past few decades, our understanding of glycan information‐encoding power has notably increased, thus leading to a significant growth also in the design and synthesis of glycomimetic probes. Combining data from multiple analytical sources, such as crystallography, nuclear magnetic resonance spectroscopy, and other biophysical methods (eg, surface plasmon resonance and carbohydrate microarrays) has allowed to shed light on the key interaction events between carbohydrates and their protein‐targets. However, the low metabolic stability of carbohydrates and their high hydrophilicity, which translates in low bioavailability, undermine their development as drugs. In this framework, the design of chemically modified analogues (called carbohydrate mimics or glycomimetics) appears as a valid alternative for the development of therapeutic agents. Glycomimetics, as structural and functional mimics of carbohydrates, can replace the native ligands in the interaction with target proteins, but are designed to show enhanced enzymatic stability and bioavailability and, possibly, an improved affinity and selectivity toward the target. In the present account, we specifically focus on the most recent advances in the design and synthesis of glycomimetics. In particular, we highlight the efforts of the scientific community in the development of straightforward synthetic procedures for the preparation of sugar mimics and in their preliminary biological evaluation.

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Activation of the glmS Ribozyme Confers Bacterial Growth Inhibition

Cited by 24 publications

References 45 publications

Functional and solution structure studies of amino sugar deacetylase and deaminase enzymes from Staphylococcus aureus

Functional and solution structure studies of amino sugar deacetylase and deaminase enzymes from Staphylococcus aureus

Self-cleavage of the glmS ribozyme core is controlled by a fragile folding element

Design and synthesis of glycomimetics: Recent advances

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