Conformational Analysis of Furanoside-Containing Mono- and Oligosaccharides

Taha, Hashem A.; Richards, Michele R.; Lowary, Todd L.

doi:10.1021/cr300249c

Cited by 121 publications

(111 citation statements)

References 554 publications

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“…The conformations assigned to the β-D-ribofuranoside 18β, the α-D-arabinofuranoside 17α, and at least for one ( o E ∼ 1 T o ∼ 1 E) of the two possible conformations in the α-D-ribofuranoside 18α are consistent with or close to those reported in the statistical analysis of crystallographic data. 103 In Tables 2 and 3, a single one of the possible conformations of the arabino-and Table 2. Antiribosomal Activities and Selectivities of the Paromomycin Equatorial Pyranosides and β-D-Furanosides (IC 50 , μg/ mL) a The partial structures in the table show the appended glycoside and ring I of paromomycin.…”

Section: Journal Of the American Chemical Societymentioning

confidence: 99%

Influence of 4′-O-Glycoside Constitution and Configuration on Ribosomal Selectivity of Paromomycin

et al. 2015

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A series of 20 4'-O-glycosides of the aminoglycoside antibiotic paromomycin were synthesized and evaluated for their ability to inhibit protein synthesis by bacterial, mitochondrial and cytosolic ribosomes. Target selectivity, i.e., inhibition of the bacterial ribosome over eukaryotic mitochondrial and cytosolic ribosomes, which is predictive of antibacterial activity with reduced ototoxicity and systemic toxicity, was greater for the equatorial than for the axial pyranosides, and greater for the d-pentopyranosides than for the l-pentopyranosides and d-hexopyranosides. In particular, 4'-O-β-d-xylopyranosyl paromomycin shows antibacterioribosomal activity comparable to that of paromomycin, but is significantly more selective showing considerably reduced affinity for the cytosolic ribosome and for the A1555G mutant mitochondrial ribosome associated with hypersusceptibility to drug-induced ototoxicity. Compound antibacterioribosomal activity correlates with antibacterial activity, and the ribosomally more active compounds show activity against Escherichia coli, Klebsiella pneumonia, Enterobacter cloacae, Acinetobacter baumannii, and methicillin-resistant Staphylococcus aureus (MRSA). The paromomycin glycosides retain activity against clinical strains of MRSA that are resistant to paromomycin, which is demonstrated to be a consequence of 4'-O-glycosylation blocking the action of 4'-aminoglycoside nucleotidyl transferases by the use of recombinant E. coli carrying the specific resistance determinant.

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Section: Journal Of the American Chemical Societymentioning

confidence: 99%

Influence of 4′-O-Glycoside Constitution and Configuration on Ribosomal Selectivity of Paromomycin

et al. 2015

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“…Furanoses are essential components in the backbone of nucleic acids (RNA and DNA) and are also frequent components of complex polysaccharides found in organisms ranging from bacteria to protozoa, fungi and plants (Taha et al 2013). Their conformational properties affect the structure and recognition of the polymers in which they are found.…”

Section: Introductionmentioning

confidence: 99%

Insights into furanose solution conformations: beyond the two-state model

Wang

Woods

2016

J Biomol NMR

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A two-state model is commonly used for interpreting ring conformations of furanoses based on NMR scalar 3J-coupling constants, with the ring populating relatively narrow distributions in the North and the South of the pseudorotation itinerary. The validity of this simple approach has been questioned, and is examined here in detail employing molecular dynamics (MD) simulations with a new GLYCAM force field parameter set for furanoses. Theoretical 3J-coupling constants derived from unrestrained MD simulations with the new furanose-specific parameters agreed with the experimental coupling constants to within 1 Hz on average. The results confirm that a two state model is a reasonable description for the ring conformation in the majority of methyl furanosides. However, in the case of methyl α-D-arabinofuranoside the ring populates a continuum of states from North to South via the eastern side of the pseudorotational itinerary. Two key properties are responsible for these differences. Firstly, East and West regions in β- and α-anomers, respectively, are destabilized by the absence of the anomeric effect. And, secondly, East or West conformations can be further destabilized by repulsive interactions among vicinal hydroxyl groups and ring oxygen atoms when the vicinal hydroxyl groups are in syn-configurations (such as in ribose and lyxose) more so than when in anti (arabinose, xylose).

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“…[40][41][42]59,60 For the latter, the Brønsted plot of log(k cat ) is usually characterized by a concave breakdown for LGs whose pK a values are above 8, this transition being indicative of a change in the rate-limiting step (from deglycosylation to glycosylation). Accordingly, for TxAbf, and more generally furanoside hydrolases, it is possible that this difference is linked to the ring strain of furanoside substrates, 61 which makes the decomposition of the glycosyl-enzyme complex (i.e., deglycosylation) more energy demanding than its creation (i.e., glycosylation). Taken together, the fact that deglycosylation is ratelimiting in TxAbf and mutants thereof, irrespective of the LG, the observation that k cat is strongly decreased in R69H-containing mutant, and the absence of relative changes in sKIE all argue in favor of a highly impaired covalent bond-breaking (deglycosylation) sub-step in the R69H-containing mutants.…”

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confidence: 99%

Molecular Design of Non-Leloir Furanose-Transferring Enzymes from an α-l-Arabinofuranosidase: A Rationale for the Engineering of Evolved Transglycosylases

et al. 2015

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The vast biodiversity of glycoside hydrolases (GHs) constitutes a reservoir of readily-available carbohydrateacting enzymes that employ simple substrates and hold the potential to perform highly stereopecific and regioselective glycosynthetic reactions. However, most GHs preferentially hydrolyze glycosidic bonds and are thus characterized by a hydrolysis/transglycosylation partition in favor of hydrolysis. Unfortunately, current knowledge is insufficient to rationally modify this partition, specifically mutating key molecular determinants to tip the balance towards transglycosylation. In this study, in the absence of precise knowledge concerning the hydrolysis/transglycosylation partition in a hydrolytic GH51 α-L-arabinofuranosidase, we describe how an iterative protein engineering approach has been used to create the first 'non-Leloir' transarabinofuranosylases. In the first step, random mutagenesis yielded a point mutation (R69H) at a position that is highly conserved in clan GH-A. Characterization of R69H revealed that this enzyme displays high transglycosylation activity, but severely reduced (61-fold) activity on pNP-α-L-arabinofuranoside. Upon recombination of R69H with other point mutations selected using semi-rational or in silico approaches, transfer rates close to 100% and transarabinofuranosylation yields of the main (1 2)-linked oligosaccharide product of 80% (vs 11% for the wild-type) were obtained. Combining data presented here with knowledge drawn from the literature, we suggest that the creation of nonLeloir transglycosylases necessarily involves the destabilization of the highly developed transition states that characterize the predominantly hydrolytic exo-acting GHs; this being an efficient way to prevent ubiquitous water molecules from performing the deglycosylation step.

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Conformational Analysis of Furanoside-Containing Mono- and Oligosaccharides

Cited by 121 publications

References 554 publications

Influence of 4′-O-Glycoside Constitution and Configuration on Ribosomal Selectivity of Paromomycin

Influence of 4′-O-Glycoside Constitution and Configuration on Ribosomal Selectivity of Paromomycin

Insights into furanose solution conformations: beyond the two-state model

Molecular Design of Non-Leloir Furanose-Transferring Enzymes from an α-l-Arabinofuranosidase: A Rationale for the Engineering of Evolved Transglycosylases

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