For Annie

Increased Activity of a Novel Low pH Folate Transporter Associated with Lipophilic Antifolate Resistance in Chinese Hamster Ovary Cells

“…The acidic pH optimum of the low pH transport route cannot be attributed to the protonation state of the ␣-and ␥-carboxyl residues of folates that have pK a values of 3.1-3.5 and 4.6 -4.8, respectively (34), since protonation would not change significantly over the pH range of 6.0 -8.0 studied. Nor, for the same reason, could the ionization of the N-1 nitrogen of the pteridine ring (pK a ϭ 2.4) be relevant to the pH dependence of transport (34,35).…”

Searching Sequence Space: Two Different Approaches to Dihydrofolate Reductase Catalysis

“…From both crystallography and NMR studies, the 2DHF/folate molecules stack near the center of the pore [16,24] in a manner perhaps similar to their solution dimeric structure. [72] From docking studies as well as monitoring interligand NOEs, the folate·NADP + complex also appears to involve stacking between the nicotinamide and pteridine rings. Thus, ring stacking might be strongly correlated with the positive cooperativity associated with 2DHF/folate and NADPH·folate complex formation.…”

Determination of dissociation constants of folic acid, methotrexate, and other photolabile pteridines by pressure-assisted capillary electrophoresis

“…Although these compounds are now classical examples of how the ligand protonation and tautomeric states impact the electrostatic and H-bond requirements of enzyme-binding geometry and the concomitant biological function, the complete and comparable sets of acid-dissociation constants (pK a values) in aqueous solution have not yet been reported, due to serious experimental problems of folic acid (poor solubility and photodegradation in wide-pH ranges) and evaluation difficulties of MTX. Partial data obtained by UV-Vis and pH-metric titrations show that (i) 4-hydroxypteridines exhibit a pK a value of approximately 8, owing to ionization of the N 3 H-C 4 O lactam group [5][6][7][8][9] and (ii) the N 1 basicity (pK a ,2.4) of 4-hydroxypteridines increases ca. 1000-fold in 4-aminopteridines [6,7].…”

“…Partial data obtained by UV-Vis and pH-metric titrations show that (i) 4-hydroxypteridines exhibit a pK a value of approximately 8, owing to ionization of the N 3 H-C 4 O lactam group [5][6][7][8][9] and (ii) the N 1 basicity (pK a ,2.4) of 4-hydroxypteridines increases ca. 1000-fold in 4-aminopteridines [6,7]. The latter fact is closely connected with inhibitor efficiency.…”