The conformation of <i>N</i>-acetyl-α-<scp>D</scp>-muramic acid and its relationship to penicillin

Knox, JE; Murthy, Niranjana

doi:10.1107/s0567740874002834

Cited by 31 publications

(4 citation statements)

References 12 publications

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“…There has been a variety of proposals on what parts of peptidoglycan is a /3-lactam antibiotic mimicking.4,5,47 Some of these proposals have been discounted or criticized. 4,5,23,48 The one receiving the most current attention is by Strominger,2,3,5 who pointed out a conformational analogy between penicillin and a D-Ala-D-Ala portion of a polypeptide which cross-links adjacent peptidoglycan polymers. This is reasonable from the point of view that the D-Ala-D-Ala peptide bond is the one that is cleaved, and D-Ala is observed to be liberated in cell wall transpeptidation.…”

Section: Resultsmentioning

confidence: 99%

Electronic structures of cephalosporins and penicillins. 4. Modeling acylation by the .beta.-lactam ring

Boyd¹,

Hermann²,

Presti³

et al. 1975

J. Med. Chem.

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Molecular orbital calculations by the CNDO/2 method are used to study the molecular and electronic details involved in the initial phases of the opening of the beta-lactam ring of a model cephalosporin structure, 7-amino-3-acetoxymethyl-3-cephem. The effect of a simple nucleophile, OH-, approaching the carbonyl carbon center of the beta-lactam ring is monitored by following the charge redistributions that occur in the bicyclic system and in the 3 side chain. A migration of electron density to the ester oxygen of the CH2OAc group is observed with concomitant weakening of the CH2-OAc bond. The results are discussed in relation to the mechanism of acylation of bacterial cell wall enzymes by beta-lactam antibiotics and in relation to the hydrolysis of these molecules. The results indicate that the ability of the 3' substituent of cephalosporins to stabilize electron density transferred to it, i.e., the leavability of the 3' moiety, can be an important factor in activating the beta-lactam toward nucleophilic attack.

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Section: Resultsmentioning

confidence: 99%

Electronic structures of cephalosporins and penicillins. 4. Modeling acylation by the .beta.-lactam ring

Boyd¹,

Hermann²,

Presti³

et al. 1975

J. Med. Chem.

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“…It is worth noting that there appears to be conformational flexibility about the C-2-N-2 bond of acetamido sugars. For example in the crystal structure of N-acetylmuramic acid there is considerable inclination of the N-acetyl plane [51°compared with 780 in aGlcNAc (Johnson, 1966)] with respect to the best plane of all six sugar-ring atoms (Knox & Murthy, 1974). The inclination of the plane in Nacetylmuramic acid results in an intramolecular hydrogen bond to the lactyl carbonyl group.…”

Section: Gd(iii)-gcnac Complexmentioning

confidence: 99%

Crystal structures of hen egg-white lysozyme complexes with gadolinium(III) and gadolinium(III)-N-acetyl-d-glucosamine

Perkins¹,

Johnson²,

Machin³

et al. 1979

Biochemical Journal

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Analysis at 0.25 nm resolution of the crystal structures of lysozyme-Gd(III) and lysozyme-Gd(III)-N-acetyl-D-glucosamine (GlcNac), prepared by diffusion methods, show that there are two main binding positions for Gd(III), one of which is close to glutamic acid-35 and the other close to aspartic acid-52. The two sites are 0.36 nm part. There is no evidence for the weak binding of Gd(III) to any of the eight other carboxy groups of lysozyme. In the presence of Gd(III), the binding of GlcNac is similar to that observed for the binding of the beta-anomer in subsite C. There are numerous small conformational changes in the protein on binding (Gd(III) and the sugar, and these have been quantified to a first approximation by real-space refinement. These changes are similar in both structures, and involve, among other small movements, shifts of one of the disulphide bridges by up to 0.05 nm. The movement of residues 70--74 observed in the binary complex of lysozyme-GlcNac [Perkins, Johnson, Machin & Phillips (1978) Biochem. J. 173-617] is not observed in the ternary complex of lysozyme-Gd(III)-GlcNac. The nature of the lysozyme-Gd(III) complex is discussed in the light of evidence from other crystallographic studies and n.m.r. solution studies. Preliminary findings for a lysozyme-Gd(III) complex prepared by co-crystallization methods are reported.

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“…Both 6-membered carbohydrate rings were constrained in the 4 C 1 chair geometry using torsion constraints based on X-ray data. , The ROE-derived distance constraints were applied as a biharmonic constraining function, and force constants for upper and lower boundaries were initially set to 20 kcal/(mol Å 2 ). The atomic velocities were applied following a Boltzmann distribution about the center of mass to obtain a starting temperature of 700 K. After simulating for 2 ps at this high temperature, the system temperature was reduced stepwise using an exponential function over a 5 ps period to reach a final temperature of 100 K. Resulting structures were sampled every 7 ps, minimized (conjugate gradient algorithm with termination criterium: gradient 0.05 kcal/(mol Å)), and stored in a separate database.…”

Section: Methodsmentioning

confidence: 99%

Structure and Dynamics of a Peptidoglycan Monomer in Aqueous Solution Using NMR Spectroscopy and Simulated Annealing Calculations

Matter¹,

Szilágyi²,

Forgó³

et al. 1997

J. Am. Chem. Soc.

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The conformation of the peptidoglycan monomer (PGM) from Brevibacterium divaricatum was determined in aqueous solution using a combined approach by 2D NMR spectroscopy, restrained simulated annealing, and molecular dynamics (MD) calculations. MD simulations in water without experimental constraints provided insights into the structure and dynamics of this glycopeptide. Hierarchical cluster analyses for conformer classifications were performed using a global molecular shape descriptor (CoMFA steric fields). Principal component analysis was subsequently employed to extract orthogonal principal conformational properties. Correlated dihedral angle mobilities were identified using a dynamic cross correlation map. The calculation of radial distribution functions for all polar protons of the molecule leads to additional information about the solvation of PGM in a protic solvent, while autocorrelation functions for dihedral angle fluctuations were used to monitor dynamic processes in different regions. From simulated annealing, a set of 11 conformers was obtained, all characterized by a well-defined extended N-terminal peptide part additionally stabilized by the bound disaccharide; the C-terminal part, on the other hand, exhibits more conformational flexibility in agreement with experimental data and MD simulations. The disaccharide conformation is in agreement with the conformational minimum computed for the model disaccharide 3-O-Me-4-O-βGlcNAc-αMurNAc using various force fields. Not only the interglycosidic bond but also the glycopeptide linkage exists in a single, well-defined conformation, for which no conformational changes can be detected during the MD simulations. In contrast, conflicting experimental data for the N-acetyl group of GlcNAc could be explained using a conformer population analysis based on ROE intensities and coupling constants accounting for a conformational equilibrium with one dominantly populated rotamer.

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The conformation of N-acetyl-α-D-muramic acid and its relationship to penicillin

Cited by 31 publications

References 12 publications

Electronic structures of cephalosporins and penicillins. 4. Modeling acylation by the .beta.-lactam ring

Electronic structures of cephalosporins and penicillins. 4. Modeling acylation by the .beta.-lactam ring

Crystal structures of hen egg-white lysozyme complexes with gadolinium(III) and gadolinium(III)-N-acetyl-d-glucosamine

Structure and Dynamics of a Peptidoglycan Monomer in Aqueous Solution Using NMR Spectroscopy and Simulated Annealing Calculations

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