Kinetics of quinine-deuterohemin binding

• Published in: Biophysical chemistry 1993-08, Vol.47 (2), p.153-162
• Main Authors: Gushimana, Y., Doepner, B., Martinez-Hackert, E., Ilgenfritz, G.
• Format: Article
• Language: English
• Subjects: Antibiotics. Antiinfectious agents. Antiparasitic agents; Antimalarial drug; Antiparasitic agents; Biological and medical sciences; Ethylene Glycols - chemistry; Hemin - analogs & derivatives; Hemin - chemistry; Hemin - metabolism; Hemin dimerization; Hydrogen-Ion Concentration; Kinetics; Medical sciences; Pharmacology. Drug treatments; Protein Binding; Quinine - chemistry; Quinine - metabolism; Quinine-hemin binding; Relaxation kinetics; Solubility; Spectrophotometry, Ultraviolet; Temperature; Water - chemistry
• ISSN: 0301-4622; 1873-4200
• DOI: 10.1016/0301-4622(93)85033-E

The interaction of quinine with free hemin is of importance for the antimalarial effect of the drug in infected erythrocytes. We have investigated the kinetics of the complex formation of quinine with deuterohemin using the temperature jump relaxation method. We use ethyleneglycol-water mixtures as a solvent, where sufficient solubility for both species is provided and dimerization of the hemins, which involves μ-oxo bridges, can be controlled. Equilibrium and kinetic data for the dimerization of deuterohemin are given at 30 and 50 vol% ethyleneglycol. Binding of quinine is significantly slower than dimerization. Both processes are well separated on the time axis and yield a relaxation progress curve which is described with high accuracy by two exponential terms. The slow relaxation process is analyzed with respect to a 1: 1 complex formation. This is the simplest mechanism which accounts for the present data, leading at 30 vol% ethyleneglycol, pH 7.5 to a binding constant of 10 4 M − and rate constants of 4.4 × 10 5 M −1 s −1 for the association and 44 s −1 for the dissociation step. However, there is evidence from the fast relaxation process that monomeric and dimeric hemin exhibit different reactivity. There is a strong decrease in rate with increasing pH. The implication of the results with respect to the proposed mechanisms of complex formation with quinoline drugs is discussed.