Interactions of metronidazole and chloramphenicol with myoglobin: Crystal structure of a Mb-acetamide product

Powell, Samantha M.; Prather, Kiana Y.; Nguyen, Nancy; Thomas, L.M.; Richter‐Addo, George B.

doi:10.1142/s1088424623500700

Cited by 2 publications

(3 citation statements)

References 30 publications

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“…Reductive activation of RNO 2 to yield heme−RNO derivatives have also been described for some nitroorganics with cytochrome P450, 8,9 horse heart (hh) 10,11 and sperm whale (sw) 12 myoglobin (Mb), human hemoglobin (Hb), 10,13 and other heme proteins; 14−21 these heme−RNO derivatives were characterized by UV−vis spectroscopy. Importantly, it has been reported that human red blood cells possess sufficient reducing capacity for the metabolic conversion of various nitroorganics.…”

Section: ■ Introductionmentioning

confidence: 99%

Insights into Nitrosoalkane Binding to Myoglobin Provided by Crystallography of Wild-Type and Distal Pocket Mutant Derivatives

et al. 2023

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Nitrosoalkanes (R−N�O; R = alkyl) are biological intermediates that form from the oxidative metabolism of various amine (RNH 2 ) drugs or from the reduction of nitroorganics (RNO 2 ). RNO compounds bind to and inhibit various heme proteins. However, structural information on the resulting Fe−RNO moieties remains limited. We report the preparation of ferrous wild-type and H64A sw Mb II −RNO derivatives (λ max 424 nm; R = Me, Et, Pr, iPr) from the reactions of Mb III −H 2 O with dithionite and nitroalkanes. The apparent extent of formation of the wt Mb derivatives followed the order MeNO > EtNO > PrNO > iPrNO, whereas the order was the opposite for the H64A derivatives. Ferricyanide oxidation of the Mb II −RNO derivatives resulted in the formation of the ferric Mb III −H 2 O precursors with loss of the RNO ligands. X-ray crystal structures of the wt Mb II −RNO derivatives at 1.76−2.0 Å resoln. revealed N-binding of RNO to Fe and the presence of H-bonding interactions between the nitroso O-atoms and distal pocket His64. The nitroso O-atoms pointed in the general direction of the protein exterior, and the hydrophobic R groups pointed toward the protein interior. X-ray crystal structures for the H64A mutant derivatives were determined at 1.74−1.80 Å resoln. An analysis of the distal pocket amino acid surface landscape provided an explanation for the differences in ligand orientations adopted by the EtNO and PrNO ligands in their wt and H64A structures. Our results provide a good baseline for the structural analysis of RNO binding to heme proteins possessing small distal pockets.

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Section: ■ Introductionmentioning

confidence: 99%

Insights into Nitrosoalkane Binding to Myoglobin Provided by Crystallography of Wild-Type and Distal Pocket Mutant Derivatives

et al. 2023

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“…[5] Recent studies have provided evidence that chloramphenicol exerts detrimental effects on both the structural integrity and functional properties of proteins, such as impeding the binding site of myoglobin. [6] Furthermore, molecular interactions between CHL and other biomolecules such as plasma proteins and bovine trypsin were also investigated. Thus, CHL exhibited a strong binding affinity towards these proteins, leading to disruption of their hydrogen bond network and subsequent alteration in folding.…”

Section: Introductionmentioning

confidence: 99%

“…It has been widely used to treat a variety of bacterial infections caused by susceptible strains, especially typhoid and paratyphoid, but also has certain hazards to humans and organisms [5] . Recent studies have provided evidence that chloramphenicol exerts detrimental effects on both the structural integrity and functional properties of proteins, such as impeding the binding site of myoglobin [6] . Furthermore, molecular interactions between CHL and other biomolecules such as plasma proteins and bovine trypsin were also investigated.…”

Section: Introductionmentioning

confidence: 99%

Effect of Chloramphenicol as Antibiotic on the Structure and Function of Pepsin and Its Mechanism of Action

Wang,

Sun,

Nie

et al. 2023

Chemistry & Biodiversity

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The interaction between chloramphenicol (CHL) and pepsin (PEP), as well as the impact of CHL on PEP conformation, were investigated using spectroscopic techniques and molecular docking simulations in this study. The experimental results demonstrate that CHL exhibits a static quenching effect on PEP. The thermodynamic parameters indicate that the reaction between CHL and PEP is spontaneous, primarily driven by hydrogen bonding and van der Waals forces. Moreover, the binding distance of r<7 nm suggests the occurrence of Förster's non‐radiative energy transfer between these two molecules. In the synchronous fluorescence spectrum, the maximum fluorescence intensity of PEP produced a redshift phenomenon, indicating that CHL was bound to tryptophan residues of PEP. The addition of CHL induces changes in the secondary structure of PEP, as confirmed by the observed alterations in peak values in three‐dimensional fluorescence spectra. The UV spectra reveal a redshift of 3 nm in the maximum absorption peak, indicating a conformational change in the secondary structure of PEP upon addition of CHL. Circular dichroism analysis demonstrates significant alterations in the α‐helix, β‐sheet, β‐turn, and random coil contents of PEP before and after CHL incorporation, further confirming its ability to modulate the secondary structure of PEP.

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Interactions of metronidazole and chloramphenicol with myoglobin: Crystal structure of a Mb-acetamide product

Cited by 2 publications

References 30 publications

Insights into Nitrosoalkane Binding to Myoglobin Provided by Crystallography of Wild-Type and Distal Pocket Mutant Derivatives

Insights into Nitrosoalkane Binding to Myoglobin Provided by Crystallography of Wild-Type and Distal Pocket Mutant Derivatives

Effect of Chloramphenicol as Antibiotic on the Structure and Function of Pepsin and Its Mechanism of Action

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