Looking at the “Alert Collector”

Polacek, Kelly Myer; Wyatt, Neal

doi:10.5860/rusq.53n3.225

Cited by 2 publications

(3 citation statements)

References 1 publication

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“…8,9 As shown in Figure 1, the formation of a peptide bond on the surface of the ribosome during peptide elongation involves activated transfer RNAs, one bound to the ribosomal P site and bearing a peptide, and the other bound to the ribosomal A site and containing an α-amino acid. 6,10,11 While the complex that results in peptide bond formation requires both protein factors and energy, formation of the peptide bond itself does not require additional energy. Peptide bond formation can be carried out in solution but the reaction is quite slow.…”

Section: Introductionmentioning

confidence: 99%

“…12 The ribosome greatly accelerates this process; ribosomal peptide bond formation is estimated to be 10 5 −10 7 -fold more rapid than the uncatalyzed reaction. 10,13 In recent years, mechanisms suggested to account for ribosomal peptide bond formation have been informed by X-ray crystal structure data. Initially, it was suggested that the mechanism involved the active participation of 23S ribosomal RNA nucleotide A2451 (E. coli nomenclature used throughout) via general acid-base catalysis, as this nucleotide had been found to be in close proximity to the 3′-CCA ends of A-site and P-site tRNA substrates.…”

Section: Introductionmentioning

confidence: 99%

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Expanding the Scope of Protein Synthesis Using Modified Ribosomes

Dedkova

Hecht

2019

J. Am. Chem. Soc.

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The ribosome produces all of the proteins and many of the peptides present in cells. As a macromolecular complex comprised of both RNAs and proteins, it employs a constituent RNA to catalyze the formation of peptide bonds rapidly and with high fidelity. Thus the ribosome can be argued to represent the key link between the RNA World, in which RNAs were the primary catalysts, and present biological systems in which protein catalysts predominate. In spite of the well known phylogenetic conservation of ribosomal RNAs through evolutionary history, ribosomal RNAs can be altered readily when placed under suitable pressure, e.g. in the presence of antibiotics which bind to functionally critical regions of rRNAs. While the structures of rRNAs have been altered intentionally for decades to enable the study of their role(s) in the mechanism of peptide bond formation, it is remarkable that the purposeful alteration of rRNA structure to enable the elaboration of proteins and peptides containing non-canonical amino acids has occurred only recently. In this Perspective, we summarize the history of rRNA modifications, and demonstrate how the intentional modification of 23S rRNA in regions critical for peptide bond formation now enables the direct ribosomal incorporation of D-amino acids, β-amino acids, dipeptides and dipeptidomimetic analogues of the normal proteinogenic L-α-amino acids. While proteins containing metabolically important functional groups such as carbohydrates and phosphate groups are normally elaborated by the post-translational modification of nascent polypeptides, the use of modified ribosomes to produce such polymers directly is also discussed. Finally, we describe the elaboration of such modified proteins both in vitro and in bacterial cells, and suggest how such novel biomaterials may be exploited in future studies.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Expanding the Scope of Protein Synthesis Using Modified Ribosomes

Dedkova

Hecht

2019

J. Am. Chem. Soc.

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“…Chloramphenicol (CAM) (Scheme 1) is an antibiotic with a wide spectrum of activity against Gram-positive and Gram-negative cocci and bacilli. 1 It is primarily bacteriostatic and works by binding to specific residues of the 23S rRNA on the 50S subunit of the bacterial ribosome, 2,3 disrupting the action of the peptidyltransferase enzyme and leading to the inhibition of important biological functions such as peptide bond formation, 4 termination of translation, 5 and translational accuracy. 6 However, treatment with CAM may be accompanied by deleterious side effects notably neurotoxicity, 7 bone marrow depletion and aplastic anemia, 8 and as a result, its use is often limited to topical ophthalmic infections and other serious infections when other suitable drugs are unavailable, such as meningitis caused by Haemophilus influenzae, Streptococcus pneumoniae, and Neisseria meningitides.…”

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confidence: 99%

Investigating the promiscuity of the chloramphenicol nitroreductase from Haemophilus influenzae towards the reduction of 4-nitrobenzene derivatives

Green

Fosso

Mayhoub

2019

Bioorganic & Medicinal Chemistry Letters

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Chloramphenicol nitroreductase (CNR), a drug-modifying enzyme from Haemophilus influenzae, has been shown to be responsible for the conversion of the nitro group into an amine in the antibiotic chloramphenicol (CAM). Since CAM structurally bears a 4-nitrobenzene moiety, we explored the substrate promiscuity of CNR by investigating its nitroreduction of 4-nitrobenzyl derivatives. We tested twenty compounds containing a nitrobenzene core, two nitropyridines, one compound with a vinylogous nitro group, and two aliphatic nitro compounds. In addition, we also synthesized twenty-eight 4-nitrobenzyl derivatives with ether, ester, and thioether substituents and assessed the relative activity of CNR in their presence. We found several of these compounds to be modified by CNR, with the enzyme activity ranging from 1-150% when compared to CAM. This data provides insights into two areas: (i) chemoenzymatic reduction of select compounds to avoid harsh chemicals and heavy metals routinely used in reductions of nitro groups and (ii) functional groups that would aid CAM in overcoming the activity of this enzyme.

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Looking at the “Alert Collector”

Cited by 2 publications

References 1 publication

Expanding the Scope of Protein Synthesis Using Modified Ribosomes

Expanding the Scope of Protein Synthesis Using Modified Ribosomes

Investigating the promiscuity of the chloramphenicol nitroreductase from Haemophilus influenzae towards the reduction of 4-nitrobenzene derivatives

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